Impact of natural products on the cholesterol transporter ABCA1

Journal Pre-proof Impact of natural products on the cholesterol transporter ABCA1 Dongdong Wang, Verena Hiebl, Tao Xu, Angela Ladurner, Atanas G. Atanasov, Elke H. Heiss, Verena M. Dirsch PII:

S0378-8741(19)32636-4

DOI:

https://doi.org/10.1016/j.jep.2019.112444

Reference:

JEP 112444

To appear in:

Journal of Ethnopharmacology

Received Date: 2 July 2019 Revised Date:

13 November 2019

Accepted Date: 29 November 2019

Please cite this article as: Wang, D., Hiebl, V., Xu, T., Ladurner, A., Atanasov, A.G., Heiss, E.H., Dirsch, V.M., Impact of natural products on the cholesterol transporter ABCA1, Journal of Ethnopharmacology (2020), doi: https://doi.org/10.1016/j.jep.2019.112444. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier B.V.

Impact

of

natural

products

on

the

cholesterol

transporter ABCA1

Dongdong Wanga,

b, 1

, Verena Hiebla, 1, Tao Xub, Angela Ladurnera, Atanas G.

Atanasova, c, d, Elke H. Heissa, Verena M. Dirscha, *

a. Department of Pharmacognosy, University of Vienna, Althanstrasse 14, 1090 Vienna, Austria. b. The Second Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Fei Shan Jie 32, 550003 Guiyang, China. c. Department of Molecular Biology, Institute of Genetics and Animal Breeding of the Polish Academy of Sciences, ul. Postepu 36A, 05-552 Jastrzębiec, Poland. d. Institute of Neurobiology, Bulgarian Academy of Sciences, 23 Acad. G. Bonchevstr., 1113 Sofia, Bulgaria. 1

These authors contributed equally.

*Corresponding author: Verena M. Dirsch, email: [email protected] T: 0043 1 4277-55270; University of Vienna, Department of Pharmacognosy, Althanstrasse 14, 1090 Vienna, Austria;

Contents Abstract ..................................................................................................................... 3 1. Introduction ........................................................................................................... 4 1.1 ATP-binding cassette transporter A1 (ABCA1) .............................................. 4 1.2 Natural products: a source for the discovery of molecules regulating ABCA1 6 2. Natural products affecting ABCA1 expression ....................................................... 8 2.1 Polyketides ................................................................................................... 9 2.1.1 Flavonoids .......................................................................................... 9 2.1.2 Non-flavonoids .................................................................................. 17 2.2 Terpenoids .................................................................................................. 19 1

2.2.1 Cineole ............................................................................................. 19 2.2.2 Zerumbone ....................................................................................... 20 2.2.3 Tanshinone IIA and Tanshindiol C ..................................................... 20 2.2.4 Andrographolide (diterpenoid lactone)............................................... 21 2.2.5 Erythrodiol......................................................................................... 21 2.2.6 Betulinic acid..................................................................................... 21 2.2.7 Saikosaponin A ................................................................................. 22 2.2.8 Panax notoginseng saponins (PNS).................................................. 22 2.2.9 Celosins ............................................................................................ 23 2.2.10 Vitamin E ........................................................................................ 23 2.2.11 Carotenoids (astaxanthin, β-carotene, retinoids, and lycopene) ...... 23 2.3 Phenylpropanoids ....................................................................................... 25 2.3.1 Lignans ............................................................................................. 25 2.3.2 Stilbenoids ........................................................................................ 26 2.3.3 α-Asarone ......................................................................................... 28 2.3.4 Chlorogenic acid ............................................................................... 28 2.3.5 Salidroside ........................................................................................ 28 2.3.6 Phenylpropanoid glucosides from Tadehagi triquetrum ..................... 29 2.3.7 Metabolites of phenylpropanoids ....................................................... 29 2.4 Tannins ....................................................................................................... 32 2.4.1 Ellagic acid........................................................................................ 32 2.4.2 Pomegranate peel polyphenols ......................................................... 32 2.4.3 PGG (1,2,3,4,6-penta-O-galloyl-β-ᴅ-glucose) .................................... 33 2.4.4 Epigallocatechin-3-gallate ................................................................. 33 2.4.5 Grape seed procyanidins .................................................................. 33 2.5 Alkaloids ..................................................................................................... 34 2.5.1 Piperine ............................................................................................ 34 2.5.2 Evodiamine and rutaecarpine (rutecarpine)....................................... 34 2.5.3 Leonurine .......................................................................................... 35 2.6 Steroids ...................................................................................................... 36 2

2.6.1 Diosgenin and methyl protodioscin ................................................... 36 2.6.2 Fucosterol ......................................................................................... 36 2.6.3 Vitamin D .......................................................................................... 36 2.7 Amino acids ................................................................................................ 37 2.7.1 Citrulline ............................................................................................ 37 2.7.2 S-allyl cysteine .................................................................................. 37 2.7.3 Taurine .............................................................................................. 37 2.8 Others ........................................................................................................ 38 2.8.1 Allicin ................................................................................................ 38 2.8.2 Astragalus polysaccharides ............................................................... 38 2.8.3 Falcarindiol ....................................................................................... 38 2.8.4 6-Gingerol ......................................................................................... 39 2.8.5 6-Dihydroparadol .............................................................................. 39 2.8.6 Paeonol ............................................................................................ 39 3. Conclusion .......................................................................................................... 40 Abbreviations .......................................................................................................... 42 References.............................................................................................................. 43

Abstract Ethnopharmacological relevance. In different countries and areas of the world, traditional medicine has been and is still used for the treatment of various disorders, including chest pain or liver complaints, of which we now know that they can be linked with altered lipid and cholesterol homeostasis. As ATP-binding cassette transporter A1 (ABCA1) plays an essential in cholesterol metabolism, its modulation may be one of the molecular mechanisms responsible for the experienced benefit of traditional recipes. Intense research activity has been dedicated to the identification of natural products from traditional medicine that regulate ABCA1 expression. Aims of the review. This review surveys natural products, originating from ethnopharmacologically used plants, fungi or marine sources, which influence ABCA1 expression, providing a reference for future study. 3

Materials and methods. Information on regulation of ABCA1 expression by natural compounds from traditional medicine was extracted from ancient and modern books, materia medica, and electronic databases (PubMed, Google Scholar, Science Direct, and ResearchGate). Results. More than 60 natural compounds from traditional medicine, especially traditional Chinese medicine (TCM), are reported to regulate ABCA1 expression in different in vitro and in vivo models (such as cholesterol efflux and atherosclerotic animal models). These active compounds belong to the classes of polyketides, terpenoids, phenylpropanoids, tannins, alkaloids, steroids, amino acids and others. Several compounds appear very promising in vivo, which need to be further investigated in animal models of diseases related to ABCA1 or in clinical studies. Conclusion. Natural products from traditional medicine constitute a large promising pool for compounds that regulate ABCA1 expression, and thus may prevent/treat diseases related to cholesterol metabolism, like atherosclerosis or Alzheimer’s disease. In many cases, the molecular mechanisms of these natural products remain to be investigated. Keywords: ABCA1; Natural products; Macrophages; Atherosclerosis; Cardiovascular disease; Cholesterol metabolism

1. Introduction 1.1 ATP-binding cassette transporter A1 (ABCA1) The ABCA1 gene, originally named ABC1, was identified by a PCR-based approach and first cloned in 1994 (Luciani et al., 1994). The human ABCA1 protein, an ATP-dependent membrane-bound transport protein, contains 2,261 amino acids with a molecular weight of 254 kDa (Figure 1). This transporter plays an essential role in mediating cellular cholesterol and phospholipid efflux (Phillips, 2014; Yokoyama, 2006) and high-density lipoprotein (HDL) biosynthesis (Brunham et al., 2006). Besides, ABCA1 has been shown to play an essential role in transporting various substrates (e.g., α-tocopherol (Oram et al., 2001), apoE (Von Eckardstein et al., 2001) and interleukin (IL)-1β (Zhou et al., 2002)) as well as phospholipid translocation (Quazi and Molday, 2013). ABCA1 was also suggested to act as a small molecule drug transporter (Gillet et al., 2004), which however requires further affirmative 4

studies. ABCA1-mediated reverse cholesterol transport (RCT), which is an important process transferring excess cholesterol from peripheral tissues to HDL and finally to the liver for bile acid synthesis and excretion, is considered to be anti-atherogenic (Wang and Tontonoz, 2018). Therefore, intensive research is aimed to understand the molecular mechanisms regulating ABCA1 expression, and to increase its abundance in order to fight/prevent disorders connected with impaired cholesterol homeostasis, such as atherosclerosis, but also Alzheimer’s disease (Koldamova et al., 2014; Wang and Tontonoz, 2018).

Figure 1. Topological diagram of human ABCA1. The model is based on several studies on human ABCA1 membrane topology (Bungert et al., 2001; Qian et al., 2017). ECD, extracellular domain; EH, extracellular helix; IH, intracellular helix; NBD, nucleotide-binding domain; PEST, a domain rich in proline, glutamic acid, serine, and threonine; R, regulatory domains; TMD, transmembrane domains.

The expression of the ABCA1 transporter can be regulated at the transcriptional, post-transcriptional and post-translational level. At the transcriptional level, ABCA1 expression is mainly controlled by nuclear receptors, such as the liver X receptor (LXR), retinoid X receptor (RXR), retinoic acid receptor (RAR), and peroxisome proliferator-activated receptor (PPAR). LXR binds to direct repeat 4 elements (DR4, direct repeat nuclear receptor-binding site with a spacing of four nucleotides) in the promoter of ABCA1 (Edwards et al., 2002) together with its permissive heterodimerization partner RXR, and then positively regulates ABCA1 expression (Song et al., 1994). Similarly, RAR also forms heterodimers with RXR and increases ABCA1 expression after promoter binding (Soprano et al., 2004). PPARα and γ were shown to stimulate ABCA1 gene transcription indirectly by activating the transcription 5

of the LXRα gene (Chawla et al., 2001; Costet et al., 2003). The regulation of ABCA1 expression by these nuclear receptors was summarized in several reviews (Edwards et al., 2002; Hiebl et al., 2018; Mutemberezi et al., 2016; Oram and Heinecke, 2005). Additionally, cytokines, such as IL, interferons (IFN), and tumor necrosis factors (TNF) have been shown to exert antinomic effects on ABCA1 gene expression (Zarubica et al., 2007).

MicroRNAs (miRNAs) are involved in post-transcriptional regulation of ABCA1 by binding to complementary sequences in the 3’-untranslated regions (3’-UTR) of ABCA1 mRNA transcripts, causing RNA destabilization or translational repression (Ambros, 2004; Bartel, 2009). To date, the 3’-UTR of the ABCA1 gene is supposed to be directly targeted by multiple miRNAs, including miRNA-9-5p (D'Amore et al., 2018), miRNA-33a and b (Rayner et al., 2010), miRNA-106b (Kim et al., 2012), miRNA-148a (Goedeke et al., 2015), and miRNA-183 (Sarver et al., 2010), among others. In addition, RNA-binding proteins (RBPs), such as human antigen R (HuR) (Ramirez et al., 2014) and nucleolin, also directly bind to the 3’-UTR of the ABCA1 gene, thereby modulating its expression. Furthermore, long noncoding RNAs (lncRNA), a large subgroup of RNAs that contain >200 nucleotides and have no apparent protein coding function, play a very important role in modulating ABCA1 protein expression at the transcriptional or post-transcriptional level. Newly identified lncRNAs, including lnc-HC (Lan et al., 2016), RP5-833A20.1 (Hu et al., 2015), and MeXis (Sallam et al., 2018) were reported to regulate ABCA1 expression.

At the post-translational level, the protein stability of ABCA1 is regulated by the proteasomal (Hsieh et al., 2014), lysosomal and calpain (thiol proteases) systems (Aleidi et al., 2015; Ogura et al., 2011; Yokoyama et al., 2012). In addition, it was shown that a sequence (amino acids 1283-1306) in the first intracellular loop of the ABCA1 protein that is rich in proline, glutamic acid, serine, and threonine (PEST motif) (Figure 1), enhances the degradation of ABCA1 (Wang et al., 2003). On the contrary, the PDZ proteins (proteins that contain the PDZ domain), α1-syntrophin and β1-syntrophin, have been shown to retard degradation of ABCA1 and to prolong the half-life of ABCA1 by binding to the PDZ binding motif in the ABCA1 protein (Munehira et al., 2004; Okuhira et al., 2005).

1.2 Natural products: a source for the discovery of molecules regulating ABCA1 6

Natural products are a promising source for the discovery of new drug leads. In comparison to synthetic compounds, they display a great structural diversity and cover a large range of biological activities. They have evolved under evolutionary pressure to interact with potential target molecules, which may account for their favorable pharmacokinetic profile (reviewed in (Hiebl et al., 2018)). Natural products do not only include compounds from plants, but also those from fungi and marine sources (reviewed in (Dias et al., 2012)). According to Cragg et al., only about 6% of the existing higher plants have been investigated pharmacologically, highlighting that there is still a lot of unexplored potential (Cragg and Newman, 2013).

Traditional medicine in different countries and areas of the world, such as traditional Chinese medicine (TCM), traditional African medicine, ancient Iranian Medicine, or Islamic medicine, is still successfully and readily used for the treatment of various disorders and diseases. Probably the most prominent traditional medicine is TCM, having a history of more than two thousand years. Diseases, such as atherosclerosis or other lipid-based disorders, are not termed as such in the ancient traditional medicine theory. However, there are some records about heart diseases in historical TCM textbooks, such as Yellow Emperor's Inner Canon (Chinese name: Huang Di Nei Jing) in the Han Dynasty (206 B.C.-220 A.D.) and the Synopsis of the Golden Chamber (Chinese name: Jin Kui Yao Lüe Fang Lun) written by Zhongjing Zhang in 219 A.D. (Wang, C. et al., 2018). The description of heart diseases in these ancient medical books refers to chest pain, pain on the back of the shoulder, and shortness of breath (especially when lying flat), which might relate to atherosclerotic cardiovascular diseases (CVD). Currently, many TCM and formulations are used to treat the typical symptoms of angina pectoris, myocardial infarction and stroke (Wang, C. et al., 2018), often without knowledge of the molecular mechanism or the bioactive principle. These traditional medicines exhibit therapeutic effects against heart diseases possibly through mediating cholesterol homeostasis via targeting ABCA1. Moreover, ABCA1 is also implicated in many other diseases, for example cancer, diabetes and Alzheimer’s disease (Koldamova et al., 2014; Smith and Land, 2012). Natural products and traditional medicines used to treat typical symptoms/conditions of these diseases were also included in this review when they were found to regulate ABCA1 expression, since they could then possibly mediate their effect via this cholesterol transporter.

In our review, we provide an overview of natural products, originating from ethnopharmacologically used plants, fungi or marine sources, which regulate ABCA1 7

expression and thus potentially influence diseases connected with disturbed cholesterol homeostasis. Where possible, we also include the proposed underlying molecular mechanism of ABCA1 regulation by these compounds.

2. Natural products affecting ABCA1 expression In this section, natural products regulating ABCA1 expression in different models are outlined. We categorized these natural products according to the biosynthetic pathways and chemical structures (i.e., polyketides, terpenoids, phenylpropanoids, tannins, alkaloids, steroids, amino acids, and others). These natural products regulating ABCA1 expression and their regulation mechanisms are summarized in Table 1 and Figure 2.

8

Figure 2. Pleiotropic regulation of ABCA1 protein expression by natural products at the transcriptional, post-transcriptional, and post-translational level.

2.1 Polyketides

2.1.1 Flavonoids Flavonoids are a class of secondary metabolites from plants and fungi possessing 15 carbon atoms that are widely present in traditional medicine.

2.1.1.1 Alpinetin 9

Ginger has been used as a traditional medicine to treat liver complaints (Shukla and Singh, 2007). A flavonoid that is present in Alpinia katsumadai Hayata and other members of the ginger family is alpinetin (7-hydroxy-5-methoxyflavanone), for which various biological activities, including anti-inflammatory effects have been described (Huo et al., 2012; Jiang et al., 2015; Liu et al., 2007). In a study using THP-1 macrophages and human monocyte-derived macrophages (HMDMs), alpinetin treatment increased mRNA and protein levels of PPARγ, LXRα and ABCA1. Knockdown experiments indicated that PPARγ and LXRα were involved in the effects of alpinetin (Jiang et al., 2015).

2.1.1.2 Anthocyanins (Cyanidin-3-O-β–glucoside, Peonidin-3-O-β–glucoside)

Anthocyanins are a very widely distributed group of flavonoids, responsible for the colors of many fruits, e.g., berry of Panax quinquefolius L. (North American ginseng), whose folkloric applications are very similar to ginseng (Nabuurs et al., 2017). Both plants have been used to treat CVD (Zhou et al., 2019). Moreover, an increased consumption of anthocyanins has been repeatedly correlated with positive health effects, including a lower risk for CVDs (reviewed in (Wallace, 2011)). In mouse peritoneal macrophages (MPMs), both cyanidin-3-O-β–glucoside (Cy-3-g) and peonidin-3-O-β–glucoside (Pn-3-g) dose-dependently led to an induction of ABCA1 gene expression, and protein expression. Further investigations revealed that the transcriptional activity of LXR and PPARγ, as well as LXRα and PPARγ mRNA levels were elevated (Xia et al., 2005).

2.1.1.3 Baicalin

A traditional Chinese drug Radix Scutellariae (Chinese name: Huang Qin), which has been used for instance to treat hypertension, consists of the dry roots of Scutellaria baicalensis Georgi (Zhao, Q. et al., 2016). A major flavonoid glycoside present in this 10

herbal drug, baicalin, has various biological activities, ranging from anti-inflammatory to anti-oxidative and anti-ischemic effects (Jung et al., 2008; Krakauer et al., 2001; Yu et al., 2016; Zhao et al., 2005). It has been shown that baicalin acted as an activator of PPARγ (Lim et al., 2012). Using a rabbit model of atherosclerosis, He et al. (He, X.W. et al., 2016) showed that baicalin could reduce the size of atherosclerotic lesions and lipid accumulation in carotid arteries. In further studies using THP-1 macrophages, the authors revealed that baicalin increased the expression of PPARγ, LXRα and ABCA1 on both the mRNA and protein levels. In agreement with He et al, also Yu et al. showed increased PPARγ and LXRα protein levels upon baicalin treatment in THP-1 macrophages (Yu et al., 2016).

2.1.1.4 Chrysin

Chrysin (5,7-dihydroxyflavone) is present in many plants, e.g. in Passiflora caerulea L, which has been used as a traditional medicine in South America for different pathologies associated with the gastrointestinal tract (Anzoise et al., 2016), but also in honey and propolis (Mani and Natesan, 2018). Chrysin was reported to have anti-diabetic, anti-inflammatory, anti-oxidative and anti-atherogenic properties (Ahad et al., 2014; Anandhi et al., 2014; Li et al., 2014; Mantawy et al., 2014; Rehman et al., 2013). It has been shown that chrysin could act as an activator of PPARγ (Feng et al., 2014). In RAW264.7 cells, chrysin activated PPARγ, and increased the mRNA levels of PPARγ, LXRα and ABCA1 (Wang, S. et al., 2015).

2.1.1.5 Hesperetin

Hesperetin is a flavonoid present in the TCM Tangerine Peel (Chinese name: Chen Pi, the dried mature pericarp of Citrus reticulate Blanco and its cultivars), which has been commonly

used

to

treat

stomach

diseases

(Zhang

et

al.,

2019).

In

hypercholesterolemic rats, hesperetin was capable of reducing the levels of plasma cholesterol (Lee et al., 1999). Hesperetin dose-dependently increased the activity of 11

LXRE (LXR response element) and ABCA1 promoter (Iio et al., 2012). It was previously published that hesperetin could activate PPARγ in a human osteosarcoma cell line (Liu et al., 2008). Another luciferase reporter gene assay indicated that in addition to LXR also PPARγ could be activated by hesperetin in THP-1 macrophages. In further experiments in the same cell line hesperetin increased both ABCA1 mRNA and protein levels (Iio et al., 2012).

2.1.1.6 Iristectorigenin

Iristectorigenin B is a constituent isolated from Belamcanda chinensis (L.) Redouté, a shrub endemic to East Asia. Belamcanda chinensis has been used for its anti-inflammatory property (Jun et al., 2012; Yamaki et al., 1990). Jun et al. showed that iristectorigenin B concentration-dependently activated both LXRα and LXRβ. In RAW264.7 macrophages, it induced the expression of ABCA1 mRNA (Jun et al., 2012). Notably, the authors of the paper always refer to iristectorigenin B in the text, whereas the structure depicted is iristectorigenin A.

2.1.1.7 Puerarin

Puerarin is present in the TCM Radix Puerariae lobatae (Chinese name: Ge Gen), the dried root of Pueraria lobata (Wild.) Ohwi, which appears helpful in hypertension (Zhang et al., 2013). Puerarin increased ABCA1 mRNA and protein levels in THP-1-derived

macrophages.

Puerarin

increased

cholesterol

efflux

in

a

dose-dependent manner and it upregulated both mRNA and protein levels of LXRα and PPARγ. The authors further showed that puerarin increased the phosphorylation of the AMP-activated kinase (AMPK) without increasing its expression. Using different inhibitors, the authors concluded that puerarin mediated its effects on ABCA1 via the AMPK-PPARγ-LXRα pathway. Puerarin reduced the levels of the miRNA-7 and increased mRNA and protein levels of the liver kinase B1 (Li et al., 2017), also known as serine/threonine kinase 11, which activated AMPK by phosphorylation (Hawley et 12

al., 2003; Woods et al., 2003). Further results of the study indicated that puerarin exerted its effect on cholesterol efflux via a cascade involving miRNA-7, liver kinase B1 and the AMPK-PPARγ-LXRα-ABCA1 pathway (Li et al., 2017).

2.1.1.8 Silymarin (isosilybin A, silybin B, silychristin, isosilychristin and taxifolin)

Silymarin, a mixture of flavonolignans, is derived from the seeds of the medicinal plant Silybum marianum (L.) Gaertn, also known as milk thistle, which has been used for centuries mainly for the treatment of liver and biliary disorders (Post-White et al., 2007). The main components of silymarin are the seven flavonolignans: silybin A, silybin B, isobilybin A, isosilybin B, silydianin, silychristin, isosilychristin and the flavonoid taxifolin (reviewed in (Polyak et al., 2013)). There are several studies suggesting hepatoprotective activity for silymarin as well as hypocholesterolemic effects (reviewed in (Krecman et al., 1998; Polyak et al., 2013; Skottova and Krecman, 1998)). In THP-1-derived macrophages, isosilybin A enhanced apolipoprotein A-I (apoA-I)-mediated cholesterol efflux, with an EC50 of 4.1 µM. Further investigations revealed that isosilybin A upregulated ABCA1 protein expression. Silybin B, silychristin and taxifolin, other components of silymarin, also enhanced the ABCA1 protein expression in THP-1 macrophages (Wang, L. et al., 2015). Interestingly, while isosilybin A partially activated PPARγ, silybin B, silychristin, isosilychristin and taxifolin were inactive on or inhibited this nuclear receptor (Pferschy-Wenzig et al., 2014; Wang, L. et al., 2015).

2.1.1.9 Wogonin

Another flavonoid wogonin was also found in the medicinal plant Scutellaria baicalensis Georgi. In J774.A1 macrophages, wogonin reduced the accumulation of lipids induced by oxLDL. In the same cell line, treatment with wogonin resulted in a dose-dependent increase in cholesterol efflux and ABCA1 protein levels. Inhibition of 13

ABCA1 with a functional inhibitor or a neutralizing antibody reversed the effects of wogonin on lipid accumulation, further suggesting an implication of ABCA1. A more detailed investigation revealed increased ABCA1 protein stability by wogonin, while mRNA levels remained unaffected (Chen et al., 2011). As the phosphorylation state of ABCA1 affects its stability (Hu et al., 2009; Martinez et al., 2003; Wang and Tall, 2003; Wang and Oram, 2005, 2007; Yamauchi et al., 2003), the ratio between phosphorylated and unphosphorylated ABCA1 was next investigated upon wogonin treatment. Wogonin reduced phosphorylation of ABCA1 at Ser/Thr sites in a time-dependent manner. In further experiments it was shown that wogonin increased the interaction between ABCA1 and protein phosphatase 2B (PP2B) for up to 60 minutes. Inhibition of PP2B significantly attenuated the effect of wogonin on ABCA1 protein

expression,

ABCA1

dephosphorylation

and

lipid

accumulation

in

macrophages, indicating a crucial role for PP2B (Chen et al., 2011).

2.1.1.10 Luteolin

A flavone that is very widespread in the plant kingdom is luteolin, which can be found in food or spices like celery, carrots and peppers, but also in medicinal plants like Reseda odorata L., used in traditional Asian medicine to treat acute myocardial infarction and hepatitis (Xiong et al., 2017). The described biological activities of luteolin range from anti-inflammatory to anticancer and antimicrobial activities, amongst others (reviewed in (Lopez-Lazaro, 2009)). Luteolin reduced lipid accumulation in RAW264.7 macrophages. ABCA1 protein levels were diminished in oxLDL-treated RAW264.7 cells and significantly increased by subsequent luteolin treatment. The authors of the study could further show that luteolin reduced the apoptotic rate that was increased by oxLDL. Moreover, oxLDL induced autophagy in this macrophage cell line, which was further intensified by luteolin. The authors concluded that the reduction in lipid accumulation, the increase in ABCA1 protein level and the reduced apoptotic rate provided by luteolin were dependent on the

14

activation of autophagy, since all these effects were reversed when the compound was co-applied with the autophagy inhibitor 3-methyladenine (Zhang et al., 2016).

2.1.1.11 Kuwanon G

Kuwanon G can be found in the root bark of the medicinal plant Morus alba L. (Nomura et al., 1982), which has been traditionally used for the treatment of various lung diseases (Min et al., 2019). Kuwanon G is a flavone derivative exerting numerous biological activities, like anti-inflammatory and neuroprotective activities (Jin et al., 2019; Kuk et al., 2017; Lee et al., 2014). In RAW264.7 macrophages, treatment with kuwanon G increased mRNA and protein levels of ABCA1. It significantly increased LXRα protein levels alone and more prominently in co-treatment with oxLDL. Usage of geranylgeranyl pyrophosphate (GGPP), a presumable inhibitor of LXR, prevented the increase in ABCA1 protein expression by kuwanon G. OxLDL also increased NF-κB p65 phosphorylation and decreased NF-κB inhibitor alpha (IκBα) degradation, which was reverted by kuwanon G co-treatment. In apoE-/- mice on a high fat diet, total cholesterol and LDL cholesterol levels in serum as well as lesion areas in the aortic sinus were decreased by kuwanon G, and lipid deposition in the atherosclerotic plaques was diminished. In the lesion area, kuwanon G reduced the macrophage content, while it did not influence the content of smooth muscle cells or collagen (Liu et al., 2018).

2.1.1.12 Quercetin

A flavonoid found in many fruits and vegetables, like apples and berries (Anand David et al., 2016), is quercetin, also present in many medicinal plants and traditional formulas, such as Yang-Yin-Qing-Fei-Tang, which is used in the therapy of pulmonary inflammation and bronchitis (Li et al., 2019). Studies reported that quercetin could lower the mortality from coronary heart disease and exert antioxidative and anti-inflammatory activities (reviewed in (Bischoff, 2008; Peluso, 2006)). Several 15

studies showed that quercetin enhanced cholesterol efflux from macrophages and increased ABCA1 mRNA and protein expression (Chang et al., 2012; Cui et al., 2017; Lee et al., 2013; Li, S. et al., 2018; Sun et al., 2015). Thereby quercetin increased the transcriptional activity of PPARγ, as well as the expression of PPARγ mRNA and protein (Lee et al., 2013; Sun et al., 2015). Regarding LXRα expression, conflicting data exist. The study by Sun et al. detected no changes in LXRα mRNA and protein levels in oxLDL-loaded THP-1 cells, while two other studies could show increased LXRα protein expression after quercetin treatment in THP-1 cells or RAW264.7 cells (Lee et al., 2013; Li, S. et al., 2018; Sun et al., 2015). In apoE-/- mice on a high-fat diet, quercetin significantly increased RCT (Cui et al., 2017). Chang et al. found that quercetin

increased

the

phosphorylation

of

transforming

growth

factor

(TGF-β)-activated kinase 1 (TAK1), which induced the phosphorylation of mitogen-activated kinase kinase 3/6 (MKK3/6), which in turn stimulated the phosphorylation of p38. Phosphorylated p38 then facilitated the binding of specificity protein 1 (Sp1) and LXRα to the promoter of ABCA1, resulting in enhanced expression of this transporter (Chang et al., 2012).

2.1.1.13 Naringenin

Naringenin is present in grapefruits and oranges, but also found in many medicinal plants, such as Curcuma longa L. that has been traditionally used for the treatment of inflammatory

diseases

(Alafiatayo

et

al.,

2019).

Naringenin

possesses

anti-inflammatory and hypocholesterolemic properties (Dall'Asta et al., 2013; Jeon et al., 2007; Saenz et al., 2018b). A recent study showed that naringenin increased the mRNA and protein levels of LXRα and the mRNA levels of ABCA1 in THP-1 macrophages. Furthermore, ABCA1 and LXRα mRNA levels were increased in human neutrophils from peripheral blood and ABCA1 mRNA expression was increased in RAW264.7 macrophages. Since naringenin had previously been shown to activate AMPK, co-application of naringenin with an AMPK inhibitor significantly diminished the effects of naringenin on LXRα mRNA and protein expression. SiRNAs 16

against AMPKα1 and AMPKα2 decreased the naringenin-mediated induction of LXRα and ABCA1 mRNA levels, further indicating that AMPK plays a role in the observed naringenin effects (Saenz et al., 2018b). Another study investigated not only naringenin, but also two phase II metabolites, naringenin-4’-O-glucuronide and naringenin-7-O-glucuronide, that were detected in urine, in regard to ABCA1 mRNA expression in M1 and M2a macrophages. In M1 macrophages, naringenin and naringenin-7-O-glucuronide increased ABCA1 mRNA levels, whereas in M2a macrophages, only naringenin induced ABCA1 mRNA expression (Dall'Asta et al., 2013).

2.1.1.14 Isoliquiritigenin

Isoliquiritigenin was isolated from the roots of Glycyrrhiza glabra L., which were traditionally used as a unique "guide drug" to enhance the effectiveness of other ingredients, to reduce toxicity, and to improve flavor in Chinese herbal formulas (Wang et al., 2013). Its biological activities range from anti-diabetic to anti-angiogenic and anti-microbial (reviewed in (Peng et al., 2015)). In MPMs treated with LPS, co-application of isoliquiritigenin increased the mRNA levels of LXRα and ABCA1. Incubation of MPMs with oxLDL (50 µg/ml) reduced the protein level of PPARγ, whereas it increased the ABCA1 protein level. When these macrophages were co-treated with oxLDL and isoliquiritigenin, PPARγ protein expression was increased whereas ABCA1 protein expression was decreased, but was still significantly higher in comparison to the untreated control. In apoE-/- mice on a Western diet, isoliquiritigenin reduced the lesion area in the aortic roots and decreased plasma total cholesterol, VLDL- and LDL-cholesterol. In the livers of the mice, isoliquiritigenin increased the mRNA levels of ABCA1, PPARγ, CYP27A1 and CYP7A1 (Du et al., 2016).

2.1.2 Non-flavonoids 2.1.2.1 Curcumin

Curcumin is present in Curcuma longa L. (turmeric or Jiang Huang), which is traditionally used to treat inflammation, and protect the function of the heart (Zang et 17

al., 2019). Curcumin increased apoA-I-mediated cholesterol efflux from J774A.1 cells and upregulated ABCA1 both at the mRNA and protein level. Furthermore, the authors showed that the half-life of ABCA1 was increased, indicating that curcumin led to a stabilization of the protein. Upon curcumin treatment, LXRα activity and ABCA1 promoter activity was increased. Further study indicated that the increase in ABCA1 expression provided by curcumin was dependent on LXRα. In a similar manner, application of an inhibitor of calmodulin led to an inhibition of the curcumin-induced expression of ABCA1 and prevented the increase in LXRα and ABCA1 promoter activity. These results suggested that calmodulin was implicated in mediating the effects of curcumin. In apoE-/- mice, atherosclerotic lesions in aortic roots were reduced upon curcumin treatment and ABCA1 protein expression in aortas was upregulated (Zhao et al., 2012).

Chen et al. (2015) used RAW264.7 macrophages, which were treated with LPS and interferon-γ (IFN-γ) to induce the M1 phenotype and then incubated with oxLDL and curcumin. They could show that curcumin led to an upregulation of PPARγ, ABCA1 and CD36 protein levels. Applying an inhibitor of PPARγ reduced the upregulation of ABCA1 and CD36 by curcumin, indicating a role for PPARγ. Interestingly, the authors also showed that in their model, curcumin promoted cholesterol uptake as well as cholesterol efflux and led to increased foam cell formation while at the same time reducing the inflammatory response (Chen et al., 2015).

Also in THP-1 macrophages, curcumin significantly increased ABCA1 mRNA and protein levels. LXRα mRNA and protein expression was increased and further experiments showed that this nuclear receptor mediated the upregulation of ABCA1 by curcumin. The protein levels of p-AMPK and p-SIRT1 were increased upon treatment with curcumin. Curcumin exerted its effects on ABCA1 expression via an AMPK-SIRT1-LXRα pathway (Lin et al., 2015). Very similar results in the same cell line were found by Sáenz et al (2018a). The authors also showed that LXRα mRNA and protein expression as well as ABCA1 mRNA were increased by curcumin. The 18

protein level of p-AMPK was increased and inhibiting AMPK reverted the effect of curcumin on LXRα mRNA and protein levels. ApoA-I-mediated cholesterol efflux was increased in THP-1 cells in the presence of curcumin (Saenz et al., 2018a). 2.1.2.2 Asperlin

Asperlin is a natural product that was isolated from a marine-derived fungus and shows anti-inflammatory activity (Lee, D.S. et al., 2011). In LPS-treated RAW264.7 macrophages, treatment with asperlin increased mRNA expression of ABCA1 and PPARγ as well as PPARγ protein expression in comparison to only LPS-treated cells. Interestingly, no effect was visible with regard to LXRα mRNA and protein expression. In apoE-/- mice fed with a cholesterol-rich diet, asperlin suppressed the formation of atherosclerotic plaques in the aorta (Zhou et al., 2017). 2.1.2.3 Emodin

Emodin is an anthraquinone derivative and present in the roots and rhizomes of Rheum palmatum L. (Chinese name: Da Huang), which is used to reduce fever and to promote blood circulation (Fu et al., 2014; Lai et al., 2015). Emodin induced ABCA1, PPARγ as well as LXRα mRNA and protein expression (Fu et al., 2014). Treatment with the PPARγ antagonist GW9662 inhibited emodin-induced upregulation of ABCA1 protein in THP-1 macrophages, suggesting that emodin mediated the increase of ABCA1 expression via the PPARγ-LXRα signaling axis (Fu et al., 2014).

2.2 Terpenoids

Terpenoids, also known as isoprenoids, are one of the largest classes of secondary metabolites present in traditional medicine. Terpenoids exhibit a wide variety of biological activities (de las Heras et al., 2003).

2.2.1 Cineole Cineole (1,8-cineole), also known as eucalyptol or cajeputol, is a terpene oxide and a principal constituent of most eucalyptus oils (Santos and Rao, 2001), and traditional 19

medicinal plants, such as Mentha longifolia L., which is widely used in traditional folk medicine for the treatment of digestive disorders (Mikaili et al., 2013). Cineole induced ABCA1 mRNA and protein expression in RAW264.7 macrophages via enhancement of both mRNA and protein expression and transactivation (in CHO-K1 cells) of LXRα and β (Jun et al., 2013). In contrast, this compound reduced the expression of LXRα mRNA and protein, and further down-regulated the expression of LXRα-responsive genes (SREBP-1c, fatty acid synthase (FAS) and stearoyl-CoA desaturase-1 (SCD1)) in the hepatic cell line HepG2 cells (Jun et al., 2013). However, the influence of cineole on ABCA1 expression in hepatocytes was not tested in this study.

2.2.2 Zerumbone Zerumbone, a cyclic sesquiterpene, is a major bioactive component of Zingiber zerumbet (L.) Smith, which is a wild ginger commonly found in Asia (Zhu and Liu, 2015). Zerumbone caused a significant induction of mRNA and protein levels of ABCA1 but not ABCG1 in THP-1 macrophages, which was associated with enhanced phosphorylation of ERK1/2 (Zhu and Liu, 2015).

2.2.3 Tanshinone IIA and Tanshindiol C Tanshinone IIA is the major bioactive lipophilic compound from the traditional medicine Danshen (the rhizome of Salvia miltiorrhiza Bunge), used to treat hepatitis, coronary artery disease and stroke (Fang et al., 2018; Xu and Liu, 2013; Zhou et al., 2005). Tanshinone IIA induced ABCA1 mRNA and protein expression in THP-1 macrophages and HMDMs likely via activation of the extracellular signal-regulated protein kinase (ERK)/nuclear factor erythroid 2 like 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway (Liu et al., 2014). Tanshinone IIA activated ERK by increased phosphorylation, induced the phosphorylation and nuclear translocation of Nrf2, and subsequently increased the expression of HO-1 (Liu et al., 2014). Furthermore, in vivo treatment with tanshinone IIA significantly up-regulated ABCA1 protein expression in the aortas of apoE−/− mice on a high-cholesterol diet and decreased atherosclerotic plaque size (Liu et al., 2014). An in vivo study indicated that sodium tanshinone IIA sulfonate treatment increased both mRNA and protein levels of ABCA1 in macrophages from Sprague-Dawley rats fed a high-fat diet.

Tanshindiol C is another bioactive compound isolated from Danshen. A recent report 20

has shown that treatment with tanshindiol C upregulated both mRNA and protein levels of ABCA1 in RAW264.7 cells through increasing sirtuin 1 (SIRT1), Nrf2 and Nrf2-co-regulated peroxiredoxin 1 (prdx1) expression (Yang et al., 2018). This study indicated that prdx1 might be a novel target for the regulation of ABCA1 expression (Yang et al., 2018).

2.2.4 Andrographolide (diterpenoid lactone) Andrographolide is a major bioactive component of Andrographis paniculate (Burm. F.) Nees,

a

plant

which

has

been

used

in

traditional

Asian

medicines.

Hypocholesterolemic effects have been described for Andrographis paniculata ((Lin et al., 2018), reviewed in (Akbar, 2011)). In J774A.1 macrophages, andrographolide increased both mRNA and protein expression of ABCA1, which was shown to bedependent on LXRα (Lin et al., 2018).

2.2.5 Erythrodiol Erythrodiol is a pentacyclic triterpenoid found in olive oil. Recently, a study showed that erythrodiol increased ABCA1 protein expression by inhibiting the ABCA1 protein degradation in THP-1-derived macrophages (Wang, L. et al., 2017c). The detailed mechanisms by which erythrodiol prevented ABCA1 degradation remain to be further investigated.

2.2.6 Betulinic acid Betulinic acid, a pentacyclic triterpenoid, is a constituent derived from the bark of yellow and white birch trees (Zhao, G.J. et al., 2013) or Tetracera potatoria, which is used extensively in ethnomedicinal practice in West Africa to treat inflammatory diseases (Oyebanji et al., 2014). Betulinic acid promoted ABCA1 expression in THP-1 macrophage-derived foam cells treated with lipopolysaccharide (LPS) via reduction of protein expression of nuclear NF-κB p65, reduced levels of phosphorylated IκBα, reduced phosphorylation of p65, and further downregulation of miRNA-33a/b (Zhao, G.J. et al., 2013). Moreover, an in vivo study showed that betulinic acid reduced miRNA-33a levels and NF-κB p65 protein expression and promoted ABCA1 protein expression in the aorta of apoE-/- mice intraperitoneally treated with LPS. Furthermore, the treated animals had reduced triglyceride, total cholesterol and LDL-cholesterol 21

levels whereas HDL-cholesterol levels were increased compared to non-treated mice (Zhao, G.J. et al., 2013). Consistently, in both RAW264.7 and THP-1 cells, betulin (a betulinic acid derivative) increased ABCA1 mRNA and protein expression. As shown in RAW264.7 macrophages, this is likely due to decreasing the nuclear protein expression of the transcriptional repressors sterol-regulatory element binding proteins (SREBPs) that can bind to E-box motifs in the ABCA1 promoter (Gui et al., 2016). In high-fat diet-fed apoE-/- mice betulin daily intragastrical administration showed a marked increase in ABCA1 protein expression in the aortic sinus and reduced lesions in en face aortas and aortic sinuses in comparison to mice only fed a high-fat diet. Plasma total cholesterol and LDL-cholesterol levels were significantly reduced by betulin treatment, while reverse cholesterol transport was increased (Gui et al., 2016).

2.2.7 Saikosaponin A Saikosaponin A, a triterpenoid glycoside (saponin), is the major bioactive constituent in the Chinese herbal medicine Radix Bupleuri (Chinese name: Chai Hu, the dried roots and rhizomes of Bupleurum chinense DC.), and used to treat hepatitis (Yang et al., 2017). Treatment with saikosaponin A enhanced ABCA1 protein expression in LPS-treated MPMs, which is likely the result of an increase in LXR transactivation and upregulation of LXRα protein level (Wei et al., 2016). Saikosaponin A enhanced ABCA1 protein expression also in THP-1 foam cells, which might be due to increasing PPARγ protein level (He, D. et al., 2016).

2.2.8 Panax notoginseng saponins (PNS) PNS are the major ingredients in Panax notoginseng (Burk.) F.H. Chen, which can be found widely in Asia where it is used cerebrovascular protection (Duan et al., 2017). PNS is a mixture of more than 20 dammarane-type saponins, including ginsenoside Rg1, Rg2, Rb1, Rb2, Rb3, Rc, Rd, Re, Rh, F2 and notoginsenoside R1, R2, R3, R4, R6, Fa, Fc, Fe, etc. (Fan et al., 2012). PNS increased both ABCA1 mRNA and protein expression in oxLDL-loaded alveolar macrophages from SD rats (NR8383) (Jia et al., 2010). Further experiments indicated that PNS-enhanced ABCA1 expression may be due to increased LXRα expression (Jia et al., 2010). In the same line, treatment with PNS also significantly increased mRNA levels of LXRα as well as enhanced the transcriptional activation of the LXRα gene promoter and led to an upregulation of ABCA1 mRNA expression in THP-1 macrophages. Moreover, Wistar rats on a 22

high-cholesterol diet and zymosan A treatment developed fewer atherosclerotic streaks and expressed higher levels of LXRα mRNA and protein in the aortas (Fan et al., 2012). It still remains to be elucidated which saponin from PNS has the most promising effect on ABCA1 expression and may contribute to the atheroprotective effect of PNS.

2.2.9 Celosins Celosin I and celosin II are triterpenoid saponins found in Semen Celosiae, the ripe seeds of Celosia argentea L., used in TCM to treat hypertension (Tang et al., 2018). Tang et al. investigated the effects of celosins (celosin I and celosin II, yielded by extraction of the dried seeds, 91.7 %) in apoE-/- mice on a high-fat diet and peritoneal macrophages. ApoE-/- mice treated with celosins developed smoother and smaller atherosclerotic plaques and the number of autophagy bodies increased in comparison to vehicle treated animals. Moreover, treated animals had reduced triglyceride, total cholesterol and LDL-cholesterol levels. In peritoneal macrophages incubated with oxLDL, treatment with celosins resulted in decreased foam cell formation and increased ABCA1 mRNA levels (Tang et al., 2018).

2.2.10 Vitamin E Vitamin E comprises two groups of compounds, namely tocopherols and tocotrienols. In each group, 4 different compounds exist, which are designated as α-, β-, γ- and δ-tocopherol or -tocotrienol. For α-tocopherol, it was shown that it can inhibit smooth muscle cell proliferation and preserve the function of endothelial cells, amongst others, which may contribute to its anti-atherogenic effect (reviewed in (Azzi and Stocker, 2000)). Bozaykut et al. (2014) studied the effect of vitamin E on atherosclerosis and its underlying mechanisms in male albino rabbits on a high cholesterol diet. They showed that supplementation with vitamin E reduced the incidence of atherosclerotic lesions significantly. Vitamin E supplementation significantly increased the mRNA levels of PPARγ and ABCA1, suggesting that vitamin E may exhibit effects through the PPARγ-LXRα-ABCA1 pathway (Bozaykut et al., 2014).

2.2.11 Carotenoids (astaxanthin, β-carotene, retinoids, and lycopene)

Astaxanthin is a naturally occurring keto-carotenoid and used as a food coloring (or 23

color additive). It is mainly found in various microorganisms and marine animals (Iizuka et al., 2012). Astaxanthin treatment transcriptionally induced ABCA1 expression in RAW264.7 cells, THP-1 macrophages and MPMs, via activation of the ABCA1 promoter in an LXR-independent manner (Iizuka et al., 2012).

Natural β-carotene, as found in carrots, comprises several isomers, including all-trans-β-carotene (all-trans-βc) and 9-cis-β-carotene (9-cis-βc). 9-cis-βc can activate RXR, and possibly increase ABCA1 expression (Zolberg Relevy et al., 2015). 9-cis-βc which is a precursor for 9-cis-retinoic acid (9-cis-RA), significantly increased both the mRNA and protein levels of ABCA1 in RAW264.7 cells through the activation of RXR, while all-trans-βc had no effect on ABCA1 mRNA levels and only slightly increased its protein levels (Bechor et al., 2016).

Retinoids are a class of chemical compounds that are vitamers of vitamin A or chemically related to it, including natural retinol (also known as Vitamin A1), and its natural derivatives 9-cis-RA and all-trans retinoic acid (ATRA). Treatment with 9-cis-RA, which is a natural ligand of RXR, increased ABCA1 expression in THP-1 derived macrophages, J774 cells, MPMs and HMDMs (Kiss et al., 2005). 9-cis-RA treatment resulted in a marked induction of ABCA1 mRNA in RAW264.7 macrophages by increasing ABCA1 promoter activity (Manna et al., 2015; Schwartz et al., 2000). 9-cis-RA also induced ABCA1 mRNA and protein expression in different types of brain cells (i.e., primary neurons, astrocytes, and microglia isolated from embryonic rat brain) in a time-dependent manner (Koldamova et al., 2003). In addition, treatment with 9-cis-RA increased ABCA1 expression and LXRα expression in J774A.1 macrophages (Zhou et al., 2015). In HEK293T cells, 9-cis-RA induced the transcriptional activity of an LXRE-luciferase construct. Furthermore, MPMs from apoE-/- mice on a high fat diet treated with 9-cis-RA had higher protein expression levels of ABCA1 and LXRα compared to the non-treated group. Moreover, the treated mice had reduced serum total and LDL cholesterol levels as well as less atherosclerotic plaque lesions in the aortic sinus (Zhou et al., 2015). The same effect was also observed with ATRA (RAR activator). ATRA treatment enhanced ABCA1 expression, both at the mRNA and protein levels in MPMs and HMDMs, which could be due to activation of the ABCA1 promoter via RARγ/RXR. In HMDMs, also LXRα mRNA was increased upon ATRA treatment (Costet et al., 2003). In RAW264.7 macrophages, treatment with ATRA resulted in increased ABCA1 protein expression via activation of LXR signaling (Manna et al., 2015). Moreover, ATRA increased levels of ABCA1 protein and mRNA in THP-1 cells, which may partly depend on the 24

induction of LXR (Wagsater et al., 2003).

Lycopene, a tetraterpene hydrocarbon which contains 11 conjugated and 2 nonconjugated double bonds (van Breemen and Pajkovic, 2008), is the most abundant carotenoid pigment in many plants and photosynthetic microorganisms (Yang et al., 2012a). Lycopene treatment enhanced ABCA1 protein expression in THP-1 cells by reduction of 3-hydroxy-3-methylglutaryl coenzyme A reductase expression, RhoA inactivation and subsequent increase in PPARγ and LXRα expression (Palozza et al., 2011). In the same line, in androgen-dependent human prostate cancer (LNCaP) cells, lycopene also elevated ABCA1 mRNA and protein expression through increasing the expression of PPARγ and LXRα (Yang et al., 2012a). Lycopene showed similar effects in the androgen-independent prostate cancer cell line DU145, where it increased ABCA1 expression via increased protein and mRNA expression of PPARγ and LXRα (Yang et al., 2012b).

2.3 Phenylpropanoids Phenylpropanoids comprise a hydroxy- and/or alkoxy-substituted aromatic phenyl moiety and a three-carbon propene tail of coumaric acid, which are widely present in traditional medicine (Barros et al., 2016).

2.3.1 Lignans Lignans, a class of natural polyphenols, are dimers derived from two molecules of a phenylpropanoid derivative (a C6-C3 monomer). They are present in a large number of traditional medicines, exhibiting various effects including anti-atherosclerotic activities (Peterson et al., 2010). 2.3.1.1 Arctigenin

Arctigenin, a phenylpropanoid dibenzylbutyrolactone lignan, is a bioactive component of Arctium lappa (Burdock), which is traditionally used to treat diseases such as sore throat and infections (Chan et al., 2011; He et al., 2018; Huang et al., 2012). Arctigenin caused a significant elevation in ABCA1 protein and mRNA levels in THP-1 macrophages, as well as a significant upregulation of PPARγ and LXRα mRNA and 25

protein (Xu et al., 2013). Further study indicated that arctigenin-upregulated ABCA1 expression was dependent on enhanced expression of PPARγ and LXRα (Xu et al., 2013). 2.3.1.2 Leoligin

Leoligin is the major natural lignan found in the alpine flower Edelweiss (Leontopodium alpinum Cass.), which has been applied to treat angina pectoris, other heart diseases, and bronchitis (Tauchen and Kokoska, 2017). Leoligin increased both protein and mRNA levels of ABCA1 in THP-1-derived macrophages (Wang et al., 2016). Further investigations indicated that leoligin did not influence ABCA1 mRNA stability, suggesting that it upregulated ABCA1 expression possibly at the transcriptional level. The detailed molecular mechanism by which leoligin regulates ABCA1 remains to be elucidated.

2.3.1.3 Honokiol

Honokiol is a biphenolic natural product, which is present in the traditional Chinese herbal medicine Magnolia bark (Hou Po, the bark from Magnolia officinalis Rehd. et Wils), which has been used to treat mood disorders (Lee, Y.J. et al., 2011; Sarris et al., 2013). In the human glioma cell line U251-MG cells, honokiol increased ABCA1 mRNA and protein expression (Jung et al., 2010). This study further confirmed that treatment with honokiol also significantly upregulated ABCA1 mRNA and protein expression levels in THP-1 macrophages, presumably by acting as RXRβ ligand and activating ABCA1 promoter activity (Jung et al., 2010). In another study it was shown that honokiol significantly activated RXRα in HEK293 cells. In RAW264.7 cells, it increased ABCA1 mRNA and protein expression and the authors showed that the increase in ABCA1 mRNA was blocked by an RXR antagonist (Kotani et al., 2010). Moreover, a high concentration of honokiol (10 mM) significantly enhanced ABCA1 mRNA and protein levels in rat primary neurons and rat primary astrocytes (Jung et al., 2010).

2.3.2 Stilbenoids

2.3.2.1 Resveratrol

26

Resveratrol is a polyphenol e.g. present in berries, nuts and red wine. Resveratrol has been assigned various properties, such as cardioprotective activity (reviewed in (Dybkowska et al., 2018; Fan et al., 2008)). In THP-1-derived macrophages and HMDMs, resveratrol increased the LXRα mRNA level. Resveratrol also increased both nuclear and cytosolic levels of LXRα protein in THP-1 cells. The mRNA level of the ABCA1 was increased upon resveratrol treatment in HMDMs as well as in THP-1 cells. Further findings suggested that the increased LXRα expression upon resveratrol treatment was at least in part due to increased binding of RNA polymerase II to the LXRα promoter (Sevov et al., 2006). A study by Voloshyna et al. (2013) confirmed the results of Sevov et al. (2006), showing that the ABCA1 and LXRα mRNA level as well as ABCA1 protein level were increased in THP-1 macrophages, human aortic endothelial cells (HAECs) and HMDMs upon resveratrol treatment. Beyond that, the authors revealed that cytochrome P450 27-hydroxylase (CYP27A1) was increased both at the mRNA and protein levels by resveratrol, which led to 27-hydroxycholestrol synthesis, which in turn acts as LXR ligand promoting cholesterol efflux. They also suggested that the effects mediated by resveratrol were dependent on PPARγ and adenosine 2A receptor pathways (Voloshyna et al., 2013).

2.3.2.2 Polydatin

Polydatin, a stilbenoid glucoside, is a constituent of Rhizoma Polygoni Cuspidati (the roots and rhizomes of Polygonum cuspidatum Sieb.et Zucc.), which has been used in TCM for the treatment of inflammation and hyperlipidemia (Hu et al., 2018). Polydatin exerts beneficial cardiovascular effects (Liu, L.T. et al., 2012). Wu et al. show that polydatin reduced oxLDL-induced cholesterol accumulation in MPMs derived from apoE-/- mice. Further experiments revealed an increase in ABCA1 and PPARγ mRNA levels upon polydatin treatment, indicating an involvement of these two proteins in the effects mediated by polydatin (Wu et al., 2015).

2.3.2.3 Other stilbenoids 27

Guo

et

al.

(2018)

identified

three

new

stilbenoids

(α,α'-dihydro-3',4,5'-trihydroxy-4'-methoxy-3-isopentenylstilbene, α,α'-dihydro-3,4',5-trihydroxy-4-methoxy-2,6-diisopentenylstilbene, α,α'-dihydro-3',4,5'-trihydroxy-4'-methoxy-2',3-diisopentenylstilbene)

and in

Cannabis

sativa L., which has a long tradition in TCM mainly for treating pain and mental illness (Brand and Zhao, 2017). These three stilbenoids increased the ABCA1 protein expression in RAW264.7 macrophages (Guo et al., 2018).

2.3.3 α-Asarone α-Asarone is a major active constituent of Acorus tatarinowii Schott, which is used against stroke (Liao et al., 2005). Treatment with α-asarone increased the expression of ABCA1 in J774A.1 macrophages exposed to oxLDL, concomitantly with an increase in RXRα mRNA (Park et al., 2015).

2.3.4 Chlorogenic acid Chlorogenic acid is a phenolic acid present in the leaves and fruits of diverse dicotyledonous plants, such as Merremia emarginata (Burm. F.), which is traditionally used as deobstruent (Angappan et al., 2018). Treatment with chlorogenic acid increased the mRNA levels of ABCA1, LXRα and PPARγ in RAW264.7 macrophages. In HEK293 cells, PPARγ transactivation was increased. In apoE-/- mice on a high-fat diet, atherosclerotic lesion area as well as triglyceride, total and LDL-cholesterol levels were reduced (Wu et al., 2014). Furthermore, three serum metabolites of chlorogenic acid (caffeic, ferulic and gallic acid) increased cholesterol efflux from RAW264.7 cells (Wu et al., 2014), which suggests that these metabolites might be the potential bioactive compounds to regulate ABCA1 expression. In the same line, a chlorogenic acid-enriched extract from Eucommia ulmoides leaves as well as chlorogenic acid itself increased mRNA expression of ABCA1 and CYP7A1 in HepG2 cells (Hao et al., 2016). With regard to LXRα, chlorogenic acid reduced the mRNA expression while the extract did not exert significant effects (Hao et al., 2016).

2.3.5 Salidroside 28

Salidroside is a constituent of the traditional medicinal plant Rhodiola rosea L., which has been used to increase physical endurance and resistance to depression, among others (Panossian et al., 2010). Salidroside upregulated the protein level of ABCA1 in THP-1-derived macrophages incubated with oxLDL. In addition, salidroside increased Nrf2 protein expression at lower concentrations (0.1 and 1 µM), whereas it decreased Nrf2 expression at concentrations from 10 µM onwards. Since the family of mitogen-activated protein kinases (MAPKs) can regulate the Nrf2 signaling pathway (Shen et al., 2004), the authors further investigated the activation of the MAPKs. Salidroside

pre-treatment

followed

by

oxLDL

incubation

increased

the

phosphorylation of Akt, while it decreased the phosphorylation of c-Jun N-terminal kinase (JNK), ERK and p38 MAPK. Thus, the authors proposed a possible implication of Akt and MAPK pathways in salidroside-mediated effects (Ni et al., 2017). However, there was no direct evidence to show the relationship between Akt or MAPK, and ABCA1.

2.3.6 Phenylpropanoid glucosides from Tadehagi triquetrum Tadehagi triquetrum (L.) H. Ohashi. is a shrub that is widespread in tropic, subtropic and Pacific regions of the world. Infusions of the roots and the leaves are used as traditional medicine in Myanmar to treat stomach discomfort (reviewed in (Aye et al., 2019)). Three phenylpropanoid glucosides from Tadehagi triquetrum reduced lipid accumulation in RAW264.7 macrophages. All three compounds led to a significantly increased ABCA1 mRNA expression. The three glucosides did not show any effect on PPARγ mRNA expression and only one compound significantly increased LXRα mRNA expression (Wang et al., 2019).

2.3.7 Metabolites of phenylpropanoids 2.3.7.1 Salicylic acid (Salicylate)

Willow bark (the bark from Salix babylonica L.) has already been used as traditional 29

medicine for thousands of years. In 1763, a first report stated the use of willow bark extract against fever and pain. The first active constituent of willow bark discovered in 1828 was salicin. Today we know that aqueous extracts of willow bark contain at least 11 related salicylate compounds, among them salicin and salicylic acid (reviewed in (Desborough and Keeling, 2017; Shara and Stohs, 2015)). It has previously been shown that salicylate is capable of directly activating AMPK in vivo and in vitro by binding to the beta subunit of the kinase (Hawley et al., 2012). To know if salicylate was able to influence cholesterol homeostasis via AMPK in macrophages, Fullerton et al. (2015) used primary bone marrow-derived macrophages (BMDMs) from wild-type (WT) and AMPK β1-deficient mice (AMPK β1-/-). Activation of AMPK by salicylate resulted in a decrease in fatty acid and sterol synthesis in WT macrophages, while no effect in AMPK β1-/- cells was observed. In acLDL-loaded macrophages, salicylate increased cholesterol efflux to both HDL and apoA-I in an AMPK β1-dependent manner and it increased the mRNA levels of ABCA1, ABCG1 and LXRα in WT but not in AMPK β1-/- macrophages. These data suggest that salicylate can modulate ABCA1 expression in macrophages via AMPK (Fullerton et al., 2015).

2.3.7.2 Protocatechuic acid (PCA)

PCA is a bioactive compound present in some medicinal herbs such as Danshen (Li, Z.M. et al., 2018). In mice, PCA is a metabolite of Cy-3-g produced by the gut microbiota. At physiologically reachable levels (0.25 - 1 µM), Cy-3-g did not increase cholesterol efflux to apoA-I or HDL, neither in MPMs, nor in THP-1 macrophages. In contrast, PCA significantly enhanced cholesterol efflux in these experimental setups. PCA also increased both ABCA1 and ABCG1 mRNA and protein expression in MPMs and THP-1 macrophages, while this was not the case for Cy-3-g. Mechanistically, PCA led to downregulation of miRNA-10b, which represses ABCA1 and ABCG1. Similar results were found in MPMs from apoE-/- mice on the AIN-93G diet. In vivo, PCA and Cy-3-g increased RCT, reduced atherosclerotic lesion area in the aortic

30

sinus and reduced cholesterol content in the whole aorta. Both in vivo and ex vivo data suggest that Cy-3-g exerts its effects via its metabolite PCA (Wang et al., 2012). 2.3.7.3 Blueberry phenolic metabolites

A high amount of polyphenols can be found in blueberries. These polyphenols are metabolized by the gut microbiota, resulting in the formation of simple phenolic compounds that are then absorbed (Kahle et al., 2006; Williamson and Clifford, 2010). In the study by Chen et al. seven phenolic acids (hippuric acid, 3-hydroxyphenylacetic acid, 3-hydroxybenzoic acid, ferulic acid, 3-(3-hydroxyphenyl)propionic acid, 3-(4-hydroxyphenyl)propionic acid, 3-hydroxycinnamic acid) were identified as metabolites in the serum of rats after a diet containing freeze-dried whole wild blueberry powder (Chen et al., 2010). A mixture of those seven phenolic acids increased both mRNA and protein levels of ABCA1 in RAW264.7 macrophages (Xie et al., 2011). Moreover, this mixture inhibited the phosphorylation of JNK, ERK1/2 and p38 MAPK induced by LPS, although at much higher concentration (Xie et al., 2011). 2.3.7.4 Danshensu

One of the active components of Danshen is the water-soluble danshensu (3-(3,4-dihydroxyphenyl)-2-hydroxypropanoic acid) (Lin and Hsieh, 2010). Treatment of RAW264.7 macrophages with danshensu increased ABCA1 mRNA and protein levels. Concomitantly, it increased PPARγ mRNA and protein expression, as well as LXRα

mRNA

expression,

which

suggests

that

danshensu

activated

the

PPARγ-LXRα-ABCA1 pathway (Gao et al., 2016). 2.3.7.5 Salvianolic acid B (lithospermic acid B or tanshinoate B)

Another compound found in Danshen is salvianolic acid B. Like danshensu, salvianolic acid B increased both mRNA and protein levels of ABCA1 in THP-1 macrophages. Further investigations revealed that both PPARγ and LXRα protein 31

levels were increased upon treatment with salvianolic acid B, showing that it may also activate the PPARγ-LXRα-ABCA1 pathway (Yue et al., 2015).

2.4 Tannins 2.4.1 Ellagic acid

Ellagic acid can be found in a variety of traditional medicines, such as pomegranate (Punica granatum L.), whose peel and roots have been commonly used in herbal remedies for treating diarrhea (Wang, D. et al., 2018b). Ellagic acid exists in plants and food in the form of ellagitannins, which are polymeric molecules belonging to the category of hydrolysable tannins. In the small intestine, ellagitannins can be hydrolyzed, yielding ellagic acid (Larrosa et al., 2010; Larrosa et al., 2006). Several pharmacological activities have been reported for ellagitannins and ellagic acid, like anti-inflammatory and anti-proliferative activities (reviewed in (Larrosa et al., 2010)). In J774A.1 macrophages, ellagic acid induced cholesterol efflux and decreased the uptake of lipids. Ellagic acid reduced scavenger receptor B1 (SR-B1) expression on both the mRNA and protein levels, whereas it upregulated ABCA1. Furthermore, the expression of the PPARγ and LXRα was induced by treatment with ellagic acid (Park et al., 2011).

2.4.2 Pomegranate peel polyphenols

Pomegranate peel polyphenols (PPP) extracted from pomegranate peel from the fruit of Punica granatum L. are mainly composed of gallic acid, α- and β-punicalagin, catechin, chorogenic acid, epicatechin and ellagic acid. PPP increased the mRNA levels of ABCA1, ABCG1, LXRα and PPARγ in RAW264.7 macrophages, whereas on the protein level only ABCA1 and LXRα expression were increased. When inhibiting LXRα by using GGPP, the induction of LXRα and ABCA1 protein expression by PPP was abolished, indicating that LXRα was involved in the effects mediated by PPP.

32

However, it has to be mentioned that GGPP alone already decreased the LXRα and ABCA1 protein expression in comparison to the control (Zhao, S. et al., 2016).

2.4.3 PGG (1,2,3,4,6-penta-O-galloyl-β-ᴅ-glucose)

PGG can be found in several plants, as for example the traditional medicinal herb Paeonia suffruticosa Andr., which has been used to treat inflammation, diabetes, angiocardiopathy (Li, S.S. et al., 2018). It has been shown that PGG has a variety of biological activities, such as inhibiting adipogenesis and reducing oxidative stress (reviewed in (Cao et al., 2014)). PGG increased ABCA1 protein levels in both THP-1 macrophages and J774 cells. Furthermore, PGG can increase cholesterol efflux to HDL, which was reduced in oxLDL-treated THP-1 and J774 cells (Zhao et al., 2015).

2.4.4 Epigallocatechin-3-gallate

A tannin abundant in green tea is epigallocatechin-3-gallate (EGCG). EGCG was capable of significantly overcoming TNF-α-induced downregulation of ABCA1 promoter activity in THP-1 foam cells. Further results suggested that TNF-α reduced ABCA1 expression via the NF-κB pathway and that EGCG inhibited the effects of TNF-α on ABCA1 via inhibiting the NF-κB pathway. It was revealed that TNF-α attenuated the DNA binding activity of Nrf2 to a human NAD(P)H quinone dehydrogenase 1 (NQO1) antioxidant response element sequence, whereas EGCG pre-treatment increased the binding of Nrf2 and the protein levels of nuclear Nrf2. Moreover, results from the study suggest that kelch like ECH associated protein 1 (Keap1) was released from its complex with Nrf2 upon EGCG treatment and interacted with inhibitor of NF-κB kinase subunit beta (IKKβ) to inhibit NF-κB function (Jiang et al., 2012).

2.4.5 Grape seed procyanidins

33

Procyanidins

exert

several

beneficial

effects,

such

as

antioxidative

and

cardioprotective activities (reviewed in (Smeriglio et al., 2017)). A grape seed procyanidin extract, containing monomeric, dimeric, trimeric, tetrameric and oligomeric procyanidins as well as phenolic acids was investigated by Terra et al. (2009). The extract could reduce lipid accumulation in RAW264.7 macrophages, as well as the expression of CD36 and increase the ABCA1 mRNA levels (Terra et al., 2009).

2.5 Alkaloids 2.5.1 Piperine

The major pungent constituent of the fruits of black pepper, Piper nigrum L., is piperine. Piperine has antioxidant and anti-diarrheal activities, amongst others (Srinivasan, 2007). Piperine led to a significant upregulation of ABCA1 protein level in THP-1-derived macrophages, whereas it did not influence ABCA1 mRNA levels. Further investigations revealed that the degradation of ABCA1 was inhibited in the presence of piperine. When investigating the implication of the three prevailing degradation pathways, namely proteasomal, lysosomal and calpain-mediated degradation, it was found that piperine most likely interfered with calpain-mediated degradation of ABCA1. Consistent with this hypothesis, calpain activity was significantly reduced after treatment with piperine (Wang, L. et al., 2017a).

2.5.2 Evodiamine and rutaecarpine (rutecarpine)

A traditional Chinese medicine Fructus Evodiae (Chinese name: Wuzhuyu) is the dry, nearly ripe fruits of Evodia rutaecarpa (Juss.) Benth, used to treat hypertension (Tang and Eisenbrand, 1992). This medicine contains the indoloquinazoline alkaloid evodiamine (Shoji et al., 1986; Wagner et al., 2011). This compound directly bound to ABCA1 and thereby increased ABCA1 stability in THP-1 macrophages, which in turn 34

led to an increased protein level of ABCA1 without altering mRNA expression (Wang, L. et al., 2018). Moreover, treatment with evodiamine reduced the size of atherosclerotic lesions, and alleviated hyperlipidaemia, as well as hepatic macrovesicular steatosis in apoE-/- mice, probably through transient receptor potential vanilloid type 1 (TRPV1) pathway (Wei et al., 2013).

Rutaecarpine is another indoloquinazoline alkaloid present in Fructus Evodiae (Chiou et al., 2011). Rutaecarpine exhibits cardiovascular effects, anti-inflammatory, anti-obesity and anticancer activities, among others (Lee et al., 2008). In RAW264.7 macrophages, HepG2 cells and primary murine macrophages from female mice, rutaecarpine upregulated ABCA1 and SR-B1 expression. In a liver cell line rutaecarpine directly bound to the LXRα-LBD and LXRβ-LBD. In apoE-/- mice under a high-fat diet, rutaecarpine reduced atherosclerotic lesions and plasma total cholesterol, LDL cholesterol and triglyceride levels (Xu et al., 2014).

2.5.3 Leonurine

Leonurine can be found in Herba Leonuri (Leonurus artemisia (Laur.) S. Y. Hu), used to treat gynaecological and obstetric disorders for thousands of years in China (Liu, X.H. et al., 2012). Leonurine attenuated atherosclerosis in hypercholesterolemic rabbits by suppressing inflammation and oxidative stress (Jiang et al., 2017; Zhang et al., 2012). Leonurine increased cholesterol efflux from THP-1-derived macrophage foam cells by increasing ABCA1 and ABCG1 mRNA and protein levels. Treatment with leonurine enhanced both mRNA and protein expression of LXRα and PPARγ, indicating that the PPARγ-LXRα signaling pathway was involved in the effect of leonurine. In apoE-/- mice, leonurine reduced atherosclerotic lesion size in aortic roots, serum triglycerides, total cholesterol and LDL cholesterol while increasing HDL cholesterol. Moreover, PPARγ, LXRα, ABCA1 and ABCG1 protein levels in aortic roots of leonurine-treated animals were increased (Jiang et al., 2017).

35

2.6 Steroids 2.6.1 Diosgenin and methyl protodioscin

The sapogenin diosgenin and its glycoside dioscin (saponin) are pharmacologically active steroidal compounds present in Dioscorea plant species. The Chinese herb Dioscorea nipponica Makino has been used to treat rheumatoid arthritis and chronic bronchitis (Ou-Yang et al., 2018). Treatment with diosgenin upregulated the expression of ABCA1 protein in THP-1 macrophage- and MPM-derived foam cells via suppressing the miRNA-19b (Lv et al., 2015). Furthermore, an in vivo study indicated that ABCA1 expression was increased in the aortic arch homogenate of apoE-/- mice treated with diosgenin. Furthermore, treated mice showed an increase in RCT and a decrease in aortic atherosclerotic lesion areas (Lv et al., 2015). In addition, methyl protodioscin treatment increased ABCA1 mRNA and protein levels in THP-1 macrophages and HepG2 cells (Ma et al., 2015). The underlying mechanism of methyl protodioscin-increased ABCA1 involved inhibited transcription of SREBP1c and SREBP2 and decreased levels of miRNA-33a/b hosted in the introns of SREBPs (Ma et al., 2015).

2.6.2 Fucosterol Fucosterol is a sterol that is abundant in marine algae (Hoang et al., 2012b). Fucosterol induced the activation of both LXRα and LXRβ as their ligand. In THP-1-derived macrophages, fucosterol increased the mRNA expression of LXRα, LXRβ and ABCA1 (Hoang et al., 2012b). Additionally, fucosterol also upregulated ABCA1 mRNA levels in Caco-2 cells and HepG2 cells (Hoang et al., 2012b).

2.6.3 Vitamin D Vitamin D is a group of fat-soluble secosteroids (i.e., steroids in which one of the bonds in the steroid rings is broken), including vitamin D3. It was demonstrated that ABCA1 protein or ABCA1 mRNA were increased in Yucatan microswine fed a vitamin D-sufficient, and a vitamin D-supplemented high-cholesterol diet, compared to a 36

vitamin D-deficient group. This might be due to an increase in 27-hydroxycholesterol and LXRα and β mRNA and/or protein expression (Yin et al., 2015). In the same line, the biologically active form of vitamin D3, 1,25(OH)2 vitamin D3, also induced upregulation of ABCA1 mRNA and protein expression, LXRα protein expression and CYP27A1 mRNA and protein expression in THP-1 macrophage-derived foam cells, which was due to a vitamin D receptor-dependent JNK1/2 signaling pathway. In HepG2 cells, ABCA1 protein expression was increased by vitamin D, as well as the expression of CYP27A1, and levels of 27-hydroxycholesterol (Yin et al., 2015). On the contrary, vitamin D receptor knockout mice showed no significant difference in ABCA1 mRNA levels in the liver compared to wild type mice (Wang et al., 2009), questioning a direct vitamin D/VDR mediated upregulation of ABCA1.

2.7 Amino acids 2.7.1 Citrulline Citrulline is unusually abundant in watermelon (Citrullus lanatus (Thunb.) Matsum. et Nakai), which is also used as a traditional medicine to treat hypertension, and diabetes, among others (Erhirhie and Ekene, 2013). Citrulline increased ABCA1 mRNA and protein levels in THP-1 macrophages via enhancing its mRNA stability (Uto-Kondo et al., 2014). Supporting the in vitro data, both ABCA1 mRNA and protein levels were also increased in HMDMs in the presence of autologous sera obtained from 8 healthy male volunteers with citrulline consumption compared to control (Uto-Kondo et al., 2014).

2.7.2 S-allyl cysteine S-allyl cysteine is an abundant bioactive compound in garlic (Allium sativum L.), which is used in traditional medicine for the treatment of CVD. S-allyl cysteine treatment was reported to increase ABCA1 mRNA and protein expression in THP-1-differentiated macrophages (Malekpour-Dehkordi et al., 2013). In this study, the high concentrations of S-allyl cysteine actually decreased THP-1 cell viability significantly from 20 mM onwards (Malekpour-Dehkordi et al., 2013).

2.7.3 Taurine

37

Taurine (2-aminoethanesulfonic acid) is a main constituent in the TCM Bezoar Bovis (dried cattle gallbladder stones), which is traditionally used to treat heart and liver disorders (Takahashi et al., 2009). In the WHO-CARDIAC study, an inverse relationship of levels of taurine excretion and the mortality from ischemic heart disease has been found (Yamori et al., 2001). Taurine increased both ABCA1 mRNA and protein levels in THP-1-derived macrophages, as well as LXRα mRNA and protein levels. In addition, taurine also increased ABCA1 mRNA in HepG2 cells and Caco-2 cells (Hoang et al., 2012a). Taurine led to a significant activation of LXRα, whereas it did not activate LXRβ (Hoang et al., 2012a).

2.8 Others 2.8.1 Allicin Allicin is a sulfur-containing compound obtained from garlic (Allium sativum L.). Recently, it was demonstrated that allicin induced upregulation of both mRNA and protein expression of ABCA1 via increasing PPARγ and LXRα protein expression in THP-1 macrophage-derived foam cells (Lin et al., 2017).

2.8.2 Astragalus polysaccharides Astragalus polysaccharides are the main active component extracted from the TCM Astragalus membranaceus (Fisch.) Bunge, used in China to treat hepatitis and modulate the immune system (Auyeung et al., 2016; Wang et al., 2010). One study indicated that Astragalus polysaccharides could rescue the downregulation of ABCA1 mRNA and protein expression induced by TNF-α in THP-1-derived foam cells (Wang et al., 2010). There was no significant alteration of ABCA1 expression when the cells were exposed to Astragalus polysaccharides alone (Wang et al., 2010). This study further suggested that the effect of Astragalus polysaccharides on ABCA1 expression could be due to attenuating the NF-κB p65 nuclear translocation induced by TNF-α (Wang et al., 2010).

2.8.3 Falcarindiol Falcarindiol is a C(17)-polyacetylene and a typical constituent of roots and rhizomes 38

of Apiaceae plants. Those include Notopterygium incisum K.C.Ting ex H.T.Chang (Chinese name: Qianghuo), which has been used to prevent painful obstructions from wind in TCM (Azietaku et al., 2017; Zschocke et al., 1997), and Aegopodium podagraria L., which is used in traditional medicine in the treatment of diabetes (Kemp, 1978; Tovchiga, 2016). A recent study showed that falcarindiol increased ABCA1 protein expression at the transcriptional and post-transcriptional levels (Wang, L. et al., 2017b). On the one hand, it seems to act via PPARγ, since a PPARγ antagonist blocked the increase in ABCA1 mRNA and protein, and on the other hand, it inhibited ABCA1 protein degradation most likely by inhibition of lysosomal cathepsins (Wang, L. et al., 2017b).

2.8.4 6-Gingerol 6-Gingerol (gingerol) is the most abundant gingerol in fresh ginger. Gingerol increased ABCA1 mRNA and protein levels in HepG2 cells, which was probably due to an increase in LXRα mRNA and protein expression (Li, X. et al., 2018).

2.8.5 6-Dihydroparadol

6-Dihydroparadol is a compound present in ginger, Zingiber officinale Roscoe (Jolad et al., 2004). Several studies exist, reporting positive effects of ginger and its constituents on metabolic disorders and on the development of CVD (reviewed in (Wang, J. et al., 2017)). 6-Dihydroparadol increased ABCA1 protein as well as ABCA1 mRNA levels in THP-1 macrophages. However, it did not lead to significant changes in LXRα, LXRβ, RXRα or PPARγ activity in HEK293 cells. Further investigations revealed that the ABCA1 protein stability in THP-1 macrophages was increased in the presence of 6-dihydroparadol, as shown by an increase in its half-life by reducing its proteasomal degradation (Wang, D. et al., 2018a).

2.8.6 Paeonol

A plant used in TCM to treat inflammatory diseases is Paeonia suffruticosa Andr. (Zhao, J.F. et al., 2013). A constituent found in Paeonia suffruticosa is paeonol, 39

shown to have anti-inflammatory and anti-proliferative activities (Huang et al., 2008; Sun et al., 2008; Zhao, J.F. et al., 2013). Paeonol did not change the expression of ABCA1 mRNA level, but increased ABCA1 protein level in RAW264.7 macrophages. Further investigation revealed that paeonol enhanced the stability of ABCA1 by inhibiting calpain activity. The reduction of calpain activity by paeonol was the result of an increased interaction of calpain with its endogenous inhibitor, calpastatin. HO-1 was required for paeonol to inhibit the activity of calpain and to increase the expression of ABCA1. Paeonol increased cholesterol efflux from RAW264.7 macrophages and reduced atherosclerotic lesion formation in apoE-/- mice on a high-fat diet, which showed an increase in ABCA1 protein in their aortas after paeonol treatment (Li et al., 2015).

A study published earlier showed that paeonol enhanced ABCA1-dependent cholesterol efflux also from J774A.1 macrophages. In this cell line paeonol increased ABCA1 protein and mRNA level of ABCA1, accompanied by increased nuclear levels of LXRα and RXRα protein. It was shown that paeonol increased the activity of the ABCA1 promoter, and activated LXRα via its ligand binding domain. In apoE-/- mice paeonol treatment decreased atherosclerotic lesion size, serum total cholesterol and triglycerides, and enhanced ABCA1 and LXRα protein expression in the aorta (Zhao, J.F. et al., 2013).

3. Conclusion For this review, a large number of reports have been summarized that identified natural products from traditional medicine, especially TCM, that regulate ABCA1 expression. Notably, many natural products regulating ABCA1 protein expression are derived from traditional medicines which are traditionally used to treat inflammatory diseases. This is not too surprising as several of the identified molecular mechanisms of action of the compounds, such as activation of LXR, PPAR or AMPK and inhibition of NF-kB signaling, affect both inflammation and lipid metabolism in macrophages. Thus, compounds from traditional medicine used for the treatment of inflammation can be very well considered for examination regarding their effect on ABCA1 40

expression.

In this review, natural products regulating ABCA1 expression in different models are outlined, including polyketides, terpenoids, phenylpropanoids, tannins, alkaloids, steroids, amino acids and others. Among them, 9-cis-βc, 9-cis-RA, ATRA, lycopene, saikosaponin A, tanshindiol C, α-asarone, cyanidin-3-O-β–glucoside, peonidin-3-O-β– glucoside, chrysin, naringenin, as well as 1,2,3,4,6-penta-O-galloyl-β-ᴅ-glucose appeared to be very active in cellular models (mainly murine and human macrophages (lines)). Thus, in vivo corroboration of their activity appears worthwhile. For some of the natural compounds, like betulinic acid, tanshinone IIA, diosgenin, rutaecarpine, leonurine, kuwanon G, curcumin, 9-cis-RA, salicylate, paeonol, polydatin, celosins, vitamin E, isoliquiritigenin and asperlin, positive in vivo studies in models for atherosclerosis already exist, which makes these compounds even more promising. The therapeutic effects of these compounds on diseases related to ABCA1 expression (e.g., atherosclerosis) still remain to be investigated in clinical studies. It has to be mentioned, though, that some studies used very high concentrations of natural products in cell models. Even if these compounds induced ABCA1 expression in cells without toxicity, the tested concentrations would be unlikely achieved in vivo. Moreover, in vivo metabolization by phase I/II enzymes or intestinal microbes are often neglected issues. Finally, in many cases the detailed molecular mechanisms of the studied natural products remain elusive or are just deduced from coincidental observations lacking experimental proof of causality. Thus, in-depth and stringent molecular analyses of active natural products may unclose new strategies for the treatment or prevention of human diseases involving ABCA1.

Acknowledgments This work was supported by the Austrian Federal Ministry of Science, Research and Economy

for

financial

support

(GZ402.000/00014-WF/V/6/2016

within

the

Sino-Austria project), the Polish KNOW (Leading National Research Centre) Scientific Consortium “Healthy Animal-Safe Food” decision of Ministry of Science and Higher Education No. 05-1/KNOW2/2015, the Peter und Traudl Engelhorn Foundation for the promotion of Life Sciences, and the Cultivation project for clinical medicine of the integrated traditional Chinese and western medicine, and Cultivation project for education team of internal medicine of the integrated traditional Chinese and western 41

medicine in the first-term subjects with special support in the first-class universities in Guizhou province (Qin Jiao Gao Fa No. 2017-158).

Author contributions Dongdong Wang, Verena Hiebl and Tao Xu reviewed the literature and drafted the manuscript. Dongdong Wang prepared the figure. Angela Ladurner, Atanas G. Atanasov, Elke H. Heiss and Verena M. Dirsch revised the manuscript.

Conflicts of Interest The authors declare no conflict of interest.

Abbreviations 3’-UTR,

3’-untranslated

regions;

9-cis-RA,

9-cis-retinoic

acid;

9-cis-βc,

9-cis-β-carotene; ABCA1, ATP-binding cassette transporter A1; acLDL, acetylated LDL;

Akt,

serine/threonine

kinase;

all-trans-βc,

all-trans-β-carotene;

AMPK,

AMP-activated kinase; apoA-I, apolipoprotein A-I; apoE, apolipoprotein E; ATRA, all-trans-retinoic acid; BMDMs, bone marrow-derived macrophages; CD36, cluster of differentiation/scavenger

receptor;

CVD,

cardiovascular

disease;

Cy-3-g,

cyanidin-3-O-β–glucoside; CYP27A1, cytochrome P450 27-hydroxylase; ECD, extracellular domain; EGCG, epigallocatechin-3-gallate; EH, extracellular helix; ERK, extracellular signal-regulated protein kinase; GGPP, geranylgeranyl pyrophosphate; HAEC, human aortic endothelial cells; HDL, high density lipoprotein; HMDMs, human monocyte-derived macrophages; HO-1, heme oxygenase 1; HuR, human antigen T; IFN, interferon; IH, intracellular helix; IKKβ, inhibitor of NF-κB kinase subunit beta; IL, interleukin; IκBα, NF-κB inhibitor alpha; JNK, c-Jun N-terminal kinase; Keap1, kelch like ECH associated protein 1; LBD, ligand binding domain; LDL, low-density lipoprotein; lncRNA, long noncoding RNA; LOX-1, Lectin-like oxLDL receptor-1; LPS, lipopolysaccharide; LXR, liver X receptor; MAPK, mitogen-activated protein kinase; miRNA, microRNA; MKK3/6, mitogen-activated kinase kinase 3/6; MPMs, mouse peritoneal

macrophages;

NBD,

nucleotide-binding

domain;

NF-κB,

nuclear

factor-kappa B; NQO1, NAD(P)H quinone dehydrogenase 1; Nrf2, nuclear factor erythroid 2 like 2; oxLDL, oxidized low density lipoprotein; PCA, protocatechuic acid; 42

PGG, 1,2,3,4,6-penta-O-galloyl-β-ᴅ-glucose; Pn-3-g, peonidin-3-O-β–glucoside; PNS, Panax notoginseng saponins; PP2B, protein phosphatase 2B; PPAR, peroxisome proliferator-activated

receptor;

PPP,

pomegranate

peel

polyphenols;

prdx1,

peroxiredoxin; R, regulatory domains; RAR, retinoic acid receptor; RBPs, RNA-binding proteins; RCT, reverse cholesterol transport; RE, response element; RhoA, ras homolog family member A; RXR, retinoid X receptor; siRNA, small interfering RNA; SIRT1, sirtuin 1; Sp1, specificity protein 1; SR, scavenger receptor; SREBP, sterol-regulatory element binding protein; TAK1, transforming growth factor-activated kinase 1; TCM, traditional Chinese medicine; TGF-β, transforming growth factor β; TMD, transmembrane domains; TNF, tumor necrosis factor.

References Ahad,

A.,

Ganai,

A.A.,

Mujeeb,

M.,

Siddiqui,

W.A.,

2014.

Chrysin,

an

anti-inflammatory molecule, abrogates renal dysfunction in type 2 diabetic rats. Toxicol Appl Pharmacol 279(1), 1-7. Akbar, S., 2011. Andrographis paniculata: a review of pharmacological activities and clinical effects. Altern Med Rev 16(1), 66-77. Alafiatayo, A.A., Lai, K.S., Syahida, A., Mahmood, M., Shaharuddin, N.A., 2019. Phytochemical Evaluation, Embryotoxicity, and Teratogenic Effects of Curcuma longa Extract on Zebrafish (Danio rerio). Evid Based Complement Alternat Med 2019, 3807207. Aleidi, S.M., Howe, V., Sharpe, L.J., Yang, A., Rao, G., Brown, A.J., Gelissen, I.C., 2015. The E3 ubiquitin ligases, HUWE1 and NEDD4-1, are involved in the post-translational regulation of the ABCG1 and ABCG4 lipid transporters. The Journal of biological chemistry 290(40), 24604-24613. Ambros, V., 2004. The functions of animal microRNAs. Nature 431(7006), 350-355. Anand David, A.V., Arulmoli, R., Parasuraman, S., 2016. Overviews of Biological Importance of Quercetin: A Bioactive Flavonoid. Pharmacogn Rev 10(20), 84-89. Anandhi, R., Thomas, P.A., Geraldine, P., 2014. Evaluation of the anti-atherogenic potential of chrysin in Wistar rats. Mol Cell Biochem 385(1-2), 103-113. Angappan, R., Devanesan, A.A., Thilagar, S., 2018. Diuretic effect of chlorogenic acid 43

from traditional medicinal plant Merremia emarginata (Burm. F.) and its by product hippuric acid. Clinical Phytoscience 4(1), 29. Anzoise, M.L., Marrassini, C., Bach, H., Gorzalczany, S., 2016. Beneficial properties of Passiflora caerulea on experimental colitis. J Ethnopharmacol 194, 137-145. Auyeung, K.K., Han, Q.B., Ko, J.K., 2016. Astragalus membranaceus: A Review of its Protection Against Inflammation and Gastrointestinal Cancers. Am J Chin Med 44(1), 1-22. Aye, M.M., Aung, H.T., Sein, M.M., Armijos, C., 2019. A Review on the Phytochemistry, Medicinal Properties and Pharmacological Activities of 15 Selected Myanmar Medicinal Plants. Molecules 24(2). Azietaku, J.T., Ma, H., Yu, X.A., Li, J., Oppong, M.B., Cao, J., An, M., Chang, Y.X., 2017. A review of the ethnopharmacology, phytochemistry and pharmacology of Notopterygium incisum. J Ethnopharmacol 202, 241-255. Azzi, A., Stocker, A., 2000. Vitamin E: non-antioxidant roles. Prog Lipid Res 39(3), 231-255. Barros, J., Serrani-Yarce, J.C., Chen, F., Baxter, D., Venables, B.J., Dixon, R.A., 2016. Role of bifunctional ammonia-lyase in grass cell wall biosynthesis. Nat Plants 2(6), 16050. Bartel, D.P., 2009. MicroRNAs: target recognition and regulatory functions. Cell 136(2), 215-233. Bechor, S., Zolberg Relevy, N., Harari, A., Almog, T., Kamari, Y., Ben-Amotz, A., Harats, D., Shaish, A., 2016. 9-cis β-Carotene Increased Cholesterol Efflux to HDL in Macrophages. Nutrients 8(7), 435. Bischoff, S.C., 2008. Quercetin: potentials in the prevention and therapy of disease. Curr Opin Clin Nutr Metab Care 11(6), 733-740. Bozaykut, P., Karademir, B., Yazgan, B., Sozen, E., Siow, R.C., Mann, G.E., Ozer, N.K., 2014. Effects of vitamin E on peroxisome proliferator-activated receptor gamma and nuclear factor-erythroid 2-related factor 2 in hypercholesterolemia-induced atherosclerosis. Free Radic Biol Med 70, 174-181. Brand, E.J., Zhao, Z., 2017. Cannabis in Chinese Medicine: Are Some Traditional 44

Indications Referenced in Ancient Literature Related to Cannabinoids? Frontiers in pharmacology 8, 108-108. Brunham, L.R., Kruit, J.K., Iqbal, J., Fievet, C., Timmins, J.M., Pape, T.D., Coburn, B.A., Bissada, N., Staels, B., Groen, A.K., Hussain, M.M., Parks, J.S., Kuipers, F., Hayden, M.R., 2006. Intestinal ABCA1 directly contributes to HDL biogenesis in vivo. J Clin Invest 116(4), 1052-1062. Bungert, S., Molday, L.L., Molday, R.S., 2001. Membrane topology of the ATP binding cassette transporter ABCR and its relationship to ABC1 and related ABCA transporters: identification of N-linked glycosylation sites. The Journal of biological chemistry 276(26), 23539-23546. Cao, Y., Himmeldirk, K.B., Qian, Y., Ren, Y., Malki, A., Chen, X., 2014. Biological and biomedical functions of Penta-O-galloyl-D-glucose and its derivatives. J Nat Med 68(3), 465-472. Chan, Y.S., Cheng, L.N., Wu, J.H., Chan, E., Kwan, Y.W., Lee, S.M., Leung, G.P., Yu, P.H., Chan, S.W., 2011. A review of the pharmacological effects of Arctium lappa (burdock). Inflammopharmacology 19(5), 245-254. Chang, Y.C., Lee, T.S., Chiang, A.N., 2012. Quercetin enhances ABCA1 expression and cholesterol efflux through a p38-dependent pathway in macrophages. J Lipid Res 53(9), 1840-1850. Chawla, A., Boisvert, W.A., Lee, C.H., Laffitte, B.A., Barak, Y., Joseph, S.B., Liao, D., Nagy, L., Edwards, P.A., Curtiss, L.K., Evans, R.M., Tontonoz, P., 2001. A PPAR gamma-LXR-ABCA1 pathway in macrophages is involved in cholesterol efflux and atherogenesis. Molecular cell 7(1), 161-171. Chen, C.Y., Shyue, S.K., Ching, L.C., Su, K.H., Wu, Y.L., Kou, Y.R., Chiang, A.N., Pan, C.C., Lee, T.S., 2011. Wogonin promotes cholesterol efflux by increasing protein phosphatase

2B-dependent

dephosphorylation

at

ATP-binding

cassette

transporter-A1 in macrophages. J Nutr Biochem 22(11), 1015-1021. Chen, F.Y., Zhou, J., Guo, N., Ma, W.G., Huang, X., Wang, H., Yuan, Z.Y., 2015. Curcumin retunes cholesterol transport homeostasis and inflammation response in M1 macrophage to prevent atherosclerosis. Biochemical and biophysical research 45

communications 467(4), 872-878. Chen, J.R., Lazarenko, O.P., Wu, X., Kang, J., Blackburn, M.L., Shankar, K., Badger, T.M., Ronis, M.J., 2010. Dietary-induced serum phenolic acids promote bone growth via p38 MAPK/beta-catenin canonical Wnt signaling. J Bone Miner Res 25(11), 2399-2411. Chiou, W.F., Ko, H.C., Wei, B.L., 2011. Evodia rutaecarpa and Three Major Alkaloids Abrogate Influenza A Virus (H1N1)-Induced Chemokines Production and Cell Migration. Evid Based Complement Alternat Med 2011, 750513. Costet, P., Lalanne, F., Gerbod-Giannone, M.C., Molina, J.R., Fu, X., Lund, E.G., Gudas, L.J., Tall, A.R., 2003. Retinoic acid receptor-mediated induction of ABCA1 in macrophages. Mol Cell Biol 23(21), 7756-7766. Cragg, G.M., Newman, D.J., 2013. Natural products: a continuing source of novel drug leads. Biochim Biophys Acta 1830(6), 3670-3695. Cui, Y., Hou, P., Li, F., Liu, Q., Qin, S., Zhou, G., Xu, X., Si, Y., Guo, S., 2017. Quercetin improves macrophage reverse cholesterol transport in apolipoprotein E-deficient mice fed a high-fat diet. Lipids Health Dis 16(1), 9. D'Amore, S., Hardfeldt, J., Cariello, M., Graziano, G., Copetti, M., Di Tullio, G., Piglionica, M., Scialpi, N., Sabba, C., Palasciano, G., Vacca, M., Moschetta, A., 2018. Identification of miR-9-5p as direct regulator of ABCA1 and HDL-driven reverse cholesterol transport in circulating CD14+ cells of patients with metabolic syndrome. Cardiovasc Res 114(8), 1154-1164. Dall'Asta, M., Derlindati, E., Curella, V., Mena, P., Calani, L., Ray, S., Zavaroni, I., Brighenti, F., Del Rio, D., 2013. Effects of naringenin and its phase II metabolites on in vitro human macrophage gene expression. Int J Food Sci Nutr 64(7), 843-849. de las Heras, B., Rodriguez, B., Bosca, L., Villar, A.M., 2003. Terpenoids: sources, structure elucidation and therapeutic potential in inflammation. Curr Top Med Chem 3(2), 171-185. Desborough, M.J.R., Keeling, D.M., 2017. The aspirin story - from willow to wonder drug. Br J Haematol 177(5), 674-683. Dias, D.A., Urban, S., Roessner, U., 2012. A historical overview of natural products in 46

drug discovery. Metabolites 2(2), 303-336. Du, F., Gesang, Q., Cao, J., Qian, M., Ma, L., Wu, D., Yu, H., 2016. Isoliquiritigenin Attenuates Atherogenesis in Apolipoprotein E-Deficient Mice. Int J Mol Sci 17(11). Duan, L., Xiong, X., Hu, J., Liu, Y., Li, J., Wang, J., 2017. Panax notoginseng Saponins for Treating Coronary Artery Disease: A Functional and Mechanistic Overview. Frontiers in pharmacology 8, 702. Dybkowska, E., Sadowska, A., Swiderski, F., Rakowska, R., Wysocka, K., 2018. The occurrence of resveratrol in foodstuffs and its potential for supporting cancer prevention and treatment. A review. Rocz Panstw Zakl Hig 69(1), 5-14. Edwards, P.A., Kast, H.R., Anisfeld, A.M., 2002. BAREing it all: the adoption of LXR and FXR and their roles in lipid homeostasis. J Lipid Res 43(1), 2-12. Erhirhie, E.O., Ekene, N.E., 2013. Medicinal Values on Citrullus lanatus (Watermelon). International Journal of Research in Pharmaceutical and Biomedical Sciences 4(4), 1305-1312. Fan, E., Zhang, L., Jiang, S., Bai, Y., 2008. Beneficial effects of resveratrol on atherosclerosis. J Med Food 11(4), 610-614. Fan, J.S., Liu, D.N., Huang, G., Xu, Z.Z., Jia, Y., Zhang, H.G., Li, X.H., He, F.T., 2012. Panax notoginseng saponins attenuate atherosclerosis via reciprocal regulation of lipid metabolism and inflammation by inducing liver X receptor alpha expression. J Ethnopharmacol 142(3), 732-738. Fang, J., Little, P.J., Xu, S., 2018. Atheroprotective Effects and Molecular Targets of Tanshinones Derived From Herbal Medicine Danshen. Medicinal research reviews 38(1), 201-228. Feng, X., Qin, H., Shi, Q., Zhang, Y., Zhou, F., Wu, H., Ding, S., Niu, Z., Lu, Y., Shen, P., 2014. Chrysin attenuates inflammation by regulating M1/M2 status via activating PPARgamma. Biochem Pharmacol 89(4), 503-514. Fu, X., Xu, A.G., Yao, M.Y., Guo, L., Zhao, L.S., 2014. Emodin enhances cholesterol efflux by activating peroxisome proliferator-activated receptor-gamma in oxidized low density

lipoprotein-loaded

THP1

macrophages.

pharmacology & physiology 41(9), 679-684. 47

Clinical

and

experimental

Fullerton, M.D., Ford, R.J., McGregor, C.P., LeBlond, N.D., Snider, S.A., Stypa, S.A., Day, E.A., Lhotak, S., Schertzer, J.D., Austin, R.C., Kemp, B.E., Steinberg, G.R., 2015. Salicylate improves macrophage cholesterol homeostasis via activation of Ampk. J Lipid Res 56(5), 1025-1033. Gao, H., Li, L., Li, L., Gong, B., Dong, P., Fordjour, P.A., Zhu, Y., Fan, G., 2016. Danshensu Promotes Cholesterol Efflux in RAW264.7 Macrophages. Lipids 51(9), 1083-1092. Gillet, J.P., Efferth, T., Steinbach, D., Hamels, J., de Longueville, F., Bertholet, V., Remacle, J., 2004. Microarray-based detection of multidrug resistance in human tumor cells by expression profiling of ATP-binding cassette transporter genes. Cancer Res 64(24), 8987-8993. Goedeke, L., Rotllan, N., Canfran-Duque, A., Aranda, J.F., Ramirez, C.M., Araldi, E., Lin, C.S., Anderson, N.N., Wagschal, A., de Cabo, R., Horton, J.D., Lasuncion, M.A., Naar, A.M., Suarez, Y., Fernandez-Hernando, C., 2015. MicroRNA-148a regulates LDL receptor and ABCA1 expression to control circulating lipoprotein levels. Nat Med 21(11), 1280-1289. Gui, Y.Z., Yan, H., Gao, F., Xi, C., Li, H.H., Wang, Y.P., 2016. Betulin attenuates atherosclerosis in apoE(-/-) mice by up-regulating ABCA1 and ABCG1. Acta pharmacologica Sinica 37(10), 1337-1348. Guo, T., Liu, Q., Hou, P., Li, F., Guo, S., Song, W., Zhang, H., Liu, X., Zhang, S., Zhang, J., Ho, C.T., Bai, N., 2018. Stilbenoids and cannabinoids from the leaves of Cannabis sativa f. sativa with potential reverse cholesterol transport activity. Food Funct 9(12), 6608-6617. Hao, S., Xiao, Y., Lin, Y., Mo, Z., Chen, Y., Peng, X., Xiang, C., Li, Y., Li, W., 2016. Chlorogenic acid-enriched extract from Eucommia ulmoides leaves inhibits hepatic lipid accumulation through regulation of cholesterol metabolism in HepG2 cells. Pharmaceutical biology 54(2), 251-259. Hawley, S.A., Boudeau, J., Reid, J.L., Mustard, K.J., Udd, L., Makela, T.P., Alessi, D.R., Hardie, D.G., 2003. Complexes between the LKB1 tumor suppressor, STRAD alpha/beta and MO25 alpha/beta are upstream kinases in the AMP-activated protein 48

kinase cascade. J Biol 2(4), 28. Hawley, S.A., Fullerton, M.D., Ross, F.A., Schertzer, J.D., Chevtzoff, C., Walker, K.J., Peggie, M.W., Zibrova, D., Green, K.A., Mustard, K.J., Kemp, B.E., Sakamoto, K., Steinberg, G.R., Hardie, D.G., 2012. The ancient drug salicylate directly activates AMP-activated protein kinase. Science 336(6083), 918-922. He, D., Wang, H., Xu, L., Wang, X., Peng, K., Wang, L., Liu, P., Qu, P., 2016. Saikosaponin-a Attenuates Oxidized LDL Uptake and Prompts Cholesterol Efflux in THP-1 Cells. J Cardiovasc Pharmacol 67(6), 510-518. He, X.W., Yu, D., Li, W.L., Zheng, Z., Lv, C.L., Li, C., Liu, P., Xu, C.Q., Hu, X.F., Jin, X.P., 2016. Anti-atherosclerotic potential of baicalin mediated by promoting cholesterol efflux from macrophages via the PPARgamma-LXRalpha-ABCA1/ABCG1 pathway. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 83, 257-264. He, Y., Fan, Q., Cai, T., Huang, W., Xie, X., Wen, Y., Shi, Z., 2018. Molecular mechanisms of the action of Arctigenin in cancer. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 108, 403-407. Hiebl, V., Ladurner, A., Latkolik, S., Dirsch, V.M., 2018. Natural products as modulators of the nuclear receptors and metabolic sensors LXR, FXR and RXR. Biotechnology Advances 36(6), 1657-1698. Hoang, M.H., Jia, Y., Jun, H.J., Lee, J.H., Hwang, K.Y., Choi, D.W., Um, S.J., Lee, B.Y., You, S.G., Lee, S.J., 2012a. Taurine is a liver X receptor-alpha ligand and activates transcription of key genes in the reverse cholesterol transport without inducing hepatic lipogenesis. Mol Nutr Food Res 56(6), 900-911. Hoang, M.H., Jia, Y., Jun, H.J., Lee, J.H., Lee, B.Y., Lee, S.J., 2012b. Fucosterol is a selective liver X receptor modulator that regulates the expression of key genes in cholesterol homeostasis in macrophages, hepatocytes, and intestinal cells. Journal of agricultural and food chemistry 60(46), 11567-11575. Hsieh, V., Kim, M.J., Gelissen, I.C., Brown, A.J., Sandoval, C., Hallab, J.C., Kockx, M., Traini, M., Jessup, W., Kritharides, L., 2014. Cellular cholesterol regulates ubiquitination and degradation of the cholesterol export proteins ABCA1 and ABCG1. 49

The Journal of biological chemistry 289(11), 7524-7536. Hu, W.H., Chan, G.K., Lou, J.S., Wu, Q.Y., Wang, H.Y., Duan, R., Cheng, M.Y., Dong, T.T., Tsim, K.W., 2018. The extract of Polygoni Cuspidati Rhizoma et Radix suppresses

the

vascular

endothelial

growth

factor-induced

angiogenesis.

Phytomedicine 42, 135-143. Hu, Y.W., Ma, X., Li, X.X., Liu, X.H., Xiao, J., Mo, Z.C., Xiang, J., Liao, D.F., Tang, C.K., 2009. Eicosapentaenoic acid reduces ABCA1 serine phosphorylation and impairs ABCA1-dependent cholesterol efflux through cyclic AMP/protein kinase A signaling pathway in THP-1 macrophage-derived foam cells. Atherosclerosis 204(2), e35-43. Hu, Y.W., Zhao, J.Y., Li, S.F., Huang, J.L., Qiu, Y.R., Ma, X., Wu, S.G., Chen, Z.P., Hu, Y.R., Yang, J.Y., Wang, Y.C., Gao, J.J., Sha, Y.H., Zheng, L., Wang, Q., 2015. RP5-833A20.1/miR-382-5p/NFIA-dependent signal transduction pathway contributes to the regulation of cholesterol homeostasis and inflammatory reaction. Arterioscler Thromb Vasc Biol 35(1), 87-101. Huang, H., Chang, E.J., Lee, Y., Kim, J.S., Kang, S.S., Kim, H.H., 2008. A genome-wide microarray analysis reveals anti-inflammatory target genes of paeonol in macrophages. Inflamm Res 57(4), 189-198. Huang, S.L., Yu, R.T., Gong, J., Feng, Y., Dai, Y.L., Hu, F., Hu, Y.H., Tao, Y.D., Leng, Y., 2012. Arctigenin, a natural compound, activates AMP-activated protein kinase via inhibition of mitochondria complex I and ameliorates metabolic disorders in ob/ob mice. Diabetologia 55(5), 1469-1481. Huo, M., Chen, N., Chi, G., Yuan, X., Guan, S., Li, H., Zhong, W., Guo, W., Soromou, L.W., Gao, R., Ouyang, H., Deng, X., Feng, H., 2012. Traditional medicine alpinetin inhibits the inflammatory response in Raw 264.7 cells and mouse models. Int Immunopharmacol 12(1), 241-248. Iio, A., Ohguchi, K., Iinuma, M., Nozawa, Y., Ito, M., 2012. Hesperetin upregulates ABCA1 expression and promotes cholesterol efflux from THP-1 macrophages. J Nat Prod 75(4), 563-566. Iizuka, M., Ayaori, M., Uto-Kondo, H., Yakushiji, E., Takiguchi, S., Nakaya, K., Hisada, T., Sasaki, M., Komatsu, T., Yogo, M., Kishimoto, Y., Kondo, K., Ikewaki, K., 2012. 50

Astaxanthin enhances ATP-binding cassette transporter A1/G1 expressions and cholesterol efflux from macrophages. J Nutr Sci Vitaminol (Tokyo) 58(2), 96-104. Jeon, S.M., Kim, H.K., Kim, H.J., Do, G.M., Jeong, T.S., Park, Y.B., Choi, M.S., 2007. Hypocholesterolemic and antioxidative effects of naringenin and its two metabolites in high-cholesterol fed rats. Transl Res 149(1), 15-21. Jia, Y., Li, Z.Y., Zhang, H.G., Li, H.B., Liu, Y., Li, X.H., 2010. Panax notoginseng saponins decrease cholesterol ester via up-regulating ATP-binding cassette transporter A1 in foam cells. J Ethnopharmacol 132(1), 297-302. Jiang, J., Mo, Z.C., Yin, K., Zhao, G.J., Lv, Y.C., Ouyang, X.P., Jiang, Z.S., Fu, Y., Tang, C.K., 2012. Epigallocatechin-3-gallate prevents TNF-alpha-induced NF-kappaB activation thereby upregulating ABCA1 via the Nrf2/Keap1 pathway in macrophage foam cells. International journal of molecular medicine 29(5), 946-956. Jiang, T., Ren, K., Chen, Q., Li, H., Yao, R., Hu, H., Lv, Y.C., Zhao, G.J., 2017. Leonurine Prevents Atherosclerosis Via Promoting the Expression of ABCA1 and ABCG1 in a Ppargamma/Lxralpha Signaling Pathway-Dependent Manner. Cell Physiol Biochem 43(4), 1703-1717. Jiang, Z., Sang, H., Fu, X., Liang, Y., Li, L., 2015. Alpinetin enhances cholesterol efflux and inhibits lipid accumulation in oxidized low-density lipoprotein-loaded human macrophages. Biotechnol Appl Biochem 62(6), 840-847. Jin, S.E., Ha, H., Shin, H.K., Seo, C.S., 2019. Anti-Allergic and Anti-Inflammatory Effects of Kuwanon G and Morusin on MC/9 Mast Cells and HaCaT Keratinocytes. Molecules 24(2). Jolad, S.D., Lantz, R.C., Solyom, A.M., Chen, G.J., Bates, R.B., Timmermann, B.N., 2004. Fresh organically grown ginger (Zingiber officinale): composition and effects on LPS-induced PGE2 production. Phytochemistry 65(13), 1937-1954. Jun, H.J., Hoang, M.H., Lee, J.W., Yaoyao, J., Lee, J.H., Lee, D.H., Lee, H.J., Seo, W.D., Hwang, B.Y., Lee, S.J., 2012. Iristectorigenin B isolated from Belamcanda chinensis is a liver X receptor modulator that increases ABCA1 and ABCG1 expression in macrophage RAW 264.7 cells. Biotechnol Lett 34(12), 2213-2221. Jun, H.J., Hoang, M.H., Yeo, S.K., Jia, Y., Lee, S.J., 2013. Induction of ABCA1 and 51

ABCG1 expression by the liver X receptor modulator cineole in macrophages. Bioorg Med Chem Lett 23(2), 579-583. Jung, C.G., Horike, H., Cha, B.Y., Uhm, K.O., Yamauchi, R., Yamaguchi, T., Hosono, T., Iida, K., Woo, J.T., Michikawa, M., 2010. Honokiol increases ABCA1 expression level by activating retinoid X receptor beta. Biological & pharmaceutical bulletin 33(7), 1105-1111. Jung, S.H., Kang, K.D., Ji, D., Fawcett, R.J., Safa, R., Kamalden, T.A., Osborne, N.N., 2008. The flavonoid baicalin counteracts ischemic and oxidative insults to retinal cells and lipid peroxidation to brain membranes. Neurochem Int 53(6-8), 325-337. Kahle, K., Kraus, M., Scheppach, W., Ackermann, M., Ridder, F., Richling, E., 2006. Studies on apple and blueberry fruit constituents: do the polyphenols reach the colon after ingestion? Mol Nutr Food Res 50(4-5), 418-423. Kemp, M.S., 1978. Falcarindiol: An antifungal polyacetylene from Aegopodium podagraria. Phytochemistry 17(5), 1002. Kim, J., Yoon, H., Ramirez, C.M., Lee, S.M., Hoe, H.S., Fernandez-Hernando, C., Kim, J., 2012. MiR-106b impairs cholesterol efflux and increases Abeta levels by repressing ABCA1 expression. Exp Neurol 235(2), 476-483. Kiss, R.S., Maric, J., Marcel, Y.L., 2005. Lipid efflux in human and mouse macrophagic cells: evidence for differential regulation of phospholipid and cholesterol efflux. J Lipid Res 46(9), 1877-1887. Koldamova, R., Fitz, N.F., Lefterov, I., 2014. ATP-binding cassette transporter A1: from metabolism to neurodegeneration. Neurobiol Dis 72 Pt A, 13-21. Koldamova, R.P., Lefterov, I.M., Ikonomovic, M.D., Skoko, J., Lefterov, P.I., Isanski, B.A., DeKosky, S.T., Lazo, J.S., 2003. 22R-hydroxycholesterol and 9-cis-retinoic acid induce ATP-binding cassette transporter A1 expression and cholesterol efflux in brain cells and decrease amyloid beta secretion. The Journal of biological chemistry 278(15), 13244-13256. Kotani, H., Tanabe, H., Mizukami, H., Makishima, M., Inoue, M., 2010. Identification of a naturally occurring rexinoid, honokiol, that activates the retinoid X receptor. J Nat Prod 73(8), 1332-1336. 52

Krakauer, T., Li, B.Q., Young, H.A., 2001. The flavonoid baicalin inhibits superantigen-induced inflammatory cytokines and chemokines. FEBS Lett 500(1-2), 52-55. Krecman, V., Skottova, N., Walterova, D., Ulrichova, J., Simanek, V., 1998. Silymarin inhibits the development of diet-induced hypercholesterolemia in rats. Planta Med 64(2), 138-142. Kuk, E.B., Jo, A.R., Oh, S.I., Sohn, H.S., Seong, S.H., Roy, A., Choi, J.S., Jung, H.A., 2017. Anti-Alzheimer's disease activity of compounds from the root bark of Morus alba L. Arch Pharm Res 40(3), 338-349. Lai, F., Zhang, Y., Xie, D.-P., Mai, S.-T., Weng, Y.-N., Du, J.-D., Wu, G.-P., Zheng, J.-X., Han, Y., 2015. A Systematic Review of Rhubarb (a Traditional Chinese Medicine) Used for the Treatment of Experimental Sepsis. Evidence-based complementary and alternative medicine : eCAM 2015, 131283-131283. Lan, X., Yan, J., Ren, J., Zhong, B., Li, J., Li, Y., Liu, L., Yi, J., Sun, Q., Yang, X., Sun, J., Meng, L., Zhu, W., Holmdahl, R., Li, D., Lu, S., 2016. A novel long noncoding RNA Lnc-HC binds hnRNPA2B1 to regulate expressions of Cyp7a1 and Abca1 in hepatocytic cholesterol metabolism. Hepatology (Baltimore, Md.) 64(1), 58-72. Larrosa, M., Garcia-Conesa, M.T., Espin, J.C., Tomas-Barberan, F.A., 2010. Ellagitannins, ellagic acid and vascular health. Mol Aspects Med 31(6), 513-539. Larrosa, M., Tomas-Barberan, F.A., Espin, J.C., 2006. The dietary hydrolysable tannin punicalagin releases ellagic acid that induces apoptosis in human colon adenocarcinoma Caco-2 cells by using the mitochondrial pathway. J Nutr Biochem 17(9), 611-625. Lee, D.S., Jeong, G.S., Li, B., Lee, S.U., Oh, H., Kim, Y.C., 2011. Asperlin from the marine-derived fungus Aspergillus sp. SF-5044 exerts anti-inflammatory effects through heme oxygenase-1 expression in murine macrophages. J Pharmacol Sci 116(3), 283-295. Lee, H.J., Ryu, J., Park, S.H., Woo, E.R., Kim, A.R., Lee, S.K., Kim, Y.S., Kim, J.O., Hong, J.H., Lee, C.J., 2014. Effects of Morus alba L. and Natural Products Including Morusin on In Vivo Secretion and In Vitro Production of Airway MUC5AC Mucin. 53

Tuberc Respir Dis (Seoul) 77(2), 65-72. Lee, S.-H., Jeong, T.-S., Park, Y.B., Kwon, Y.-K., Choi, M.-S., Bok, S.-H., 1999. Hypocholesterolemic

effect

of

hesperetin

mediated

by

inhibition

of

3-hydroxy-3-methylgultaryl coenzyme a reductase and acyl coenzyme a: Cholesterol acyltransferase in rats fed high-cholesterol diet. Nutrition Research 19(8), 1245-1258. Lee, S.H., Son, J.K., Jeong, B.S., Jeong, T.C., Chang, H.W., Lee, E.S., Jahng, Y., 2008. Progress in the studies on rutaecarpine. Molecules 13(2), 272-300. Lee, S.M., Moon, J., Cho, Y., Chung, J.H., Shin, M.J., 2013. Quercetin up-regulates expressions of peroxisome proliferator-activated receptor gamma, liver X receptor alpha, and ATP binding cassette transporter A1 genes and increases cholesterol efflux in human macrophage cell line. Nutr Res 33(2), 136-143. Lee, Y.J., Lee, Y.M., Lee, C.K., Jung, J.K., Han, S.B., Hong, J.T., 2011. Therapeutic applications of compounds in the Magnolia family. Pharmacol Ther 130(2), 157-176. Li, C.H., Gong, D., Chen, L.Y., Zhang, M., Xia, X.D., Cheng, H.P., Huang, C., Zhao, Z.W., Zheng, X.L., Tang, X.E., Tang, C.K., 2017. Puerarin promotes ABCA1-mediated cholesterol efflux and decreases cellular lipid accumulation in THP-1 macrophages. European journal of pharmacology 811, 74-86. Li, H., Tan, L., Zhang, J.W., Chen, H., Liang, B., Qiu, T., Li, Q.S., Cai, M., Zhang, Q.H., 2019. Quercetin is the Active Component of Yang-Yin-Qing-Fei-Tang to Induce Apoptosis in Non-Small Cell Lung Cancer. Am J Chin Med 47(4), 879-893. Li, R., Zang, A., Zhang, L., Zhang, H., Zhao, L., Qi, Z., Wang, H., 2014. Chrysin ameliorates diabetes-associated cognitive deficits in Wistar rats. Neurol Sci 35(10), 1527-1532. Li, S., Cao, H., Shen, D., Jia, Q., Chen, C., Xing, S.L., 2018. Quercetin protects against oxLDLinduced injury via regulation of ABCAl, LXRalpha and PCSK9 in RAW264.7 macrophages. Mol Med Rep 18(1), 799-806. Li, S.S., Wu, Q., Yin, D.D., Feng, C.Y., Liu, Z.A., Wang, L.S., 2018. Phytochemical variation among the traditional Chinese medicine Mu Dan Pi from Paeonia suffruticosa (tree peony). Phytochemistry 146, 16-24. Li, X., Guo, J., Liang, N., Jiang, X., Song, Y., Ou, S., Hu, Y., Jiao, R., Bai, W., 2018. 54

6-Gingerol Regulates Hepatic Cholesterol Metabolism by Up-regulation of LDLR and Cholesterol Efflux-Related Genes in HepG2 Cells. Frontiers in pharmacology 9, 159. Li, X., Zhou, Y., Yu, C., Yang, H., Zhang, C., Ye, Y., Xiao, S., 2015. Paeonol suppresses lipid accumulation in macrophages via upregulation of the ATPbinding cassette transporter A1 and downregulation of the cluster of differentiation 36. Int J Oncol 46(2), 764-774. Li, Z.M., Xu, S.W., Liu, P.Q., 2018. Salvia miltiorrhizaBurge (Danshen): a golden herbal medicine in cardiovascular therapeutics. Acta pharmacologica Sinica 39(5), 802-824. Liao, W.-P., Chen, L., Yi, Y.-H., Sun, W.-W., Gao, M.-M., Su, T., Yang, S.-Q., 2005. Study of Antiepileptic Effect of Extracts from Acorus tatarinowii Schott. Epilepsia 46(s1), 21-24. Lim, H.A., Lee, E.K., Kim, J.M., Park, M.H., Kim, D.H., Choi, Y.J., Ha, Y.M., Yoon, J.H., Choi, J.S., Yu, B.P., Chung, H.Y., 2012. PPARgamma activation by baicalin suppresses NF-kappaB-mediated inflammation in aged rat kidney. Biogerontology 13(2), 133-145. Lin, H.C., Lii, C.K., Chen, H.C., Lin, A.H., Yang, Y.C., Chen, H.W., 2018. Andrographolide Inhibits Oxidized LDL-Induced Cholesterol Accumulation and Foam Cell Formation in Macrophages. Am J Chin Med 46(1), 87-106. Lin, T.H., Hsieh, C.L., 2010. Pharmacological effects of Salvia miltiorrhiza (Danshen) on cerebral infarction. Chin Med 5, 22. Lin, X.L., Hu, H.J., Liu, Y.B., Hu, X.M., Fan, X.J., Zou, W.W., Pan, Y.Q., Zhou, W.Q., Peng, M.W., Gu, C.H., 2017. Allicin induces the upregulation of ABCA1 expression via PPARgamma/LXRalpha signaling in THP-1 macrophage-derived foam cells. International journal of molecular medicine 39(6), 1452-1460. Lin, X.L., Liu, M.H., Hu, H.J., Feng, H.R., Fan, X.J., Zou, W.W., Pan, Y.Q., Hu, X.M., Wang, Z., 2015. Curcumin enhanced cholesterol efflux by upregulating ABCA1 expression through AMPK-SIRT1-LXRalpha signaling in THP-1 macrophage-derived foam cells. DNA Cell Biol 34(9), 561-572. Liu, L., Chen, X., Hu, Z., 2007. Separation and determination of alpinetin and 55

cardamonin in Alpinia katsumadai Hayata by flow injection-micellar electrokinetic chromatography. Talanta 71(1), 155-159. Liu, L., Shan, S., Zhang, K., Ning, Z.Q., Lu, X.P., Cheng, Y.Y., 2008. Naringenin and hesperetin, two flavonoids derived from Citrus aurantium up-regulate transcription of adiponectin. Phytother Res 22(10), 1400-1403. Liu, L.T., Guo, G., Wu, M., Zhang, W.G., 2012. The progress of the research on cardio-vascular effects and acting mechanism of polydatin. Chin J Integr Med 18(9), 714-719. Liu, X.H., Pan, L.L., Zhu, Y.Z., 2012. Active chemical compounds of traditional Chinese medicine Herba Leonuri: implications for cardiovascular diseases. Clinical and experimental pharmacology & physiology 39(3), 274-282. Liu, X.X., Zhang, X.W., Wang, K., Wang, X.Y., Ma, W.L., Cao, W., Mo, D., Sun, Y., Li, X.Q.,

2018.

Kuwanon

G

attenuates

atherosclerosis

by

upregulation

of

LXRalpha-ABCA1/ABCG1 and inhibition of NFkappaB activity in macrophages. Toxicol Appl Pharmacol 341, 56-63. Liu, Z., Wang, J., Huang, E., Gao, S., Li, H., Lu, J., Tian, K., Little, P.J., Shen, X., Xu, S., Liu, P., 2014. Tanshinone IIA suppresses cholesterol accumulation in human macrophages: role of heme oxygenase-1. J Lipid Res 55(2), 201-213. Lopez-Lazaro, M., 2009. Distribution and biological activities of the flavonoid luteolin. Mini Rev Med Chem 9(1), 31-59. Luciani, M.F., Denizot, F., Savary, S., Mattei, M.G., Chimini, G., 1994. Cloning of Two Novel ABC Transporters Mapping on Human Chromosome 9. Genomics 21(1), 150-159. Lv, Y.C., Yang, J., Yao, F., Xie, W., Tang, Y.Y., Ouyang, X.P., He, P.P., Tan, Y.L., Li, L., Zhang, M., Liu, D., Cayabyab, F.S., Zheng, X.L., Tang, C.K., 2015. Diosgenin inhibits atherosclerosis via suppressing the MiR-19b-induced downregulation of ATP-binding cassette transporter A1. Atherosclerosis 240(1), 80-89. Ma, W., Ding, H., Gong, X., Liu, Z., Lin, Y., Zhang, Z., Lin, G., 2015. Methyl protodioscin increases ABCA1 expression and cholesterol efflux while inhibiting gene expressions for synthesis of cholesterol and triglycerides by suppressing SREBP 56

transcription and microRNA 33a/b levels. Atherosclerosis 239(2), 566-570. Malekpour-Dehkordi, Z., Javadi, E., Doosti, M., Paknejad, M., Nourbakhsh, M., Yassa, N., Gerayesh-Nejad, S., Heshmat, R., 2013. S-Allylcysteine, a garlic compound, increases ABCA1 expression in human THP-1 macrophages. Phytother Res 27(3), 357-361. Mani, R., Natesan, V., 2018. Chrysin: Sources, beneficial pharmacological activities, and molecular mechanism of action. Phytochemistry 145, 187-196. Manna, P.R., Sennoune, S.R., Martinez-Zaguilan, R., Slominski, A.T., Pruitt, K., 2015. Regulation of retinoid mediated cholesterol efflux involves liver X receptor activation in mouse macrophages. Biochemical and biophysical research communications 464(1), 312-317. Mantawy, E.M., El-Bakly, W.M., Esmat, A., Badr, A.M., El-Demerdash, E., 2014. Chrysin alleviates acute doxorubicin cardiotoxicity in rats via suppression of oxidative stress, inflammation and apoptosis. European journal of pharmacology 728, 107-118. Martinez, L.O., Agerholm-Larsen, B., Wang, N., Chen, W., Tall, A.R., 2003. Phosphorylation of a pest sequence in ABCA1 promotes calpain degradation and is reversed by ApoA-I. The Journal of biological chemistry 278(39), 37368-37374. Mikaili, P., Mojaverrostami, S., Moloudizargari, M., Aghajanshakeri, S., 2013. Pharmacological and therapeutic effects of Mentha Longifolia L. and its main constituent, menthol. Anc Sci Life 33(2), 131-138. Min, T.R., Park, H.J., Park, M.N., Kim, B., Park, S.H., 2019. The Root Bark of Morus alba L. Suppressed the Migration of Human Non-Small-Cell Lung Cancer Cells through Inhibition of Epithelial(-)Mesenchymal Transition Mediated by STAT3 and Src. Int J Mol Sci 20(9). Munehira, Y., Ohnishi, T., Kawamoto, S., Furuya, A., Shitara, K., Imamura, M., Yokota, T., Takeda, S., Amachi, T., Matsuo, M., Kioka, N., Ueda, K., 2004. Alpha1-syntrophin modulates turnover of ABCA1. The Journal of biological chemistry 279(15), 15091-15095. Mutemberezi, V., Guillemot-Legris, O., Muccioli, G.G., 2016. Oxysterols: From cholesterol metabolites to key mediators. Prog Lipid Res 64, 152-169. 57

Nabuurs, M.H., McCallum, J.L., Brown, D.C., Kirby, C.W., 2017. NMR characterization of novel pyranoanthocyanins derived from the pulp of Panax quinquefolius L. (North American ginseng). Magn Reson Chem 55(3), 177-182. Ni, J., Li, Y., Li, W., Guo, R., 2017. Salidroside protects against foam cell formation and apoptosis, possibly via the MAPK and AKT signaling pathways. Lipids Health Dis 16(1), 198. Nomura, T., Fukai, T., Matsumoto, J., Ohmori, T., 1982. Constituents of the cultivated mulberry tree. Planta Med 46(1), 28-32. Ogura, M., Ayaori, M., Terao, Y., Hisada, T., Iizuka, M., Takiguchi, S., Uto-Kondo, H., Yakushiji, E., Nakaya, K., Sasaki, M., Komatsu, T., Ozasa, H., Ohsuzu, F., Ikewaki, K., 2011. Proteasomal inhibition promotes ATP-binding cassette transporter A1 (ABCA1) and ABCG1 expression and cholesterol efflux from macrophages in vitro and in vivo. Arterioscler Thromb Vasc Biol 31(9), 1980-1987. Okuhira, K., Fitzgerald, M.L., Sarracino, D.A., Manning, J.J., Bell, S.A., Goss, J.L., Freeman, M.W., 2005. Purification of ATP-binding cassette transporter A1 and associated binding proteins reveals the importance of beta1-syntrophin in cholesterol efflux. The Journal of biological chemistry 280(47), 39653-39664. Oram, J.F., Heinecke, J.W., 2005. ATP-binding cassette transporter A1: a cell cholesterol exporter that protects against cardiovascular disease. Physiol Rev 85(4), 1343-1372. Oram, J.F., Vaughan, A.M., Stocker, R., 2001. ATP-binding cassette transporter A1 mediates cellular secretion of alpha-tocopherol. The Journal of biological chemistry 276(43), 39898-39902. Ou-Yang, S.H., Jiang, T., Zhu, L., Yi, T., 2018. Dioscorea nipponica Makino: a systematic review on its ethnobotany, phytochemical and pharmacological profiles. Chem Cent J 12(1), 57. Oyebanji, B.O., Saba, A.B., Oridupa, O.A., 2014. Studies on the anti-inflammatory, analgesic and antipyrexic activities of betulinic acid derived from Tetracera potatoria. Afr J Tradit Complement Altern Med 11(1), 30-33. Palozza, P., Simone, R., Catalano, A., Parrone, N., Monego, G., Ranelletti, F.O., 2011. 58

Lycopene regulation of cholesterol synthesis and efflux in human macrophages. J Nutr Biochem 22(10), 971-978. Panossian, A., Wikman, G., Sarris, J., 2010. Rosenroot (Rhodiola rosea): traditional use, chemical composition, pharmacology and clinical efficacy. Phytomedicine 17(7), 481-493. Park, S.H., Kim, J.L., Lee, E.S., Han, S.Y., Gong, J.H., Kang, M.K., Kang, Y.H., 2011. Dietary ellagic acid attenuates oxidized LDL uptake and stimulates cholesterol efflux in murine macrophages. J Nutr 141(11), 1931-1937. Park, S.H., Paek, J.H., Shin, D., Lee, J.Y., Lim, S.S., Kang, Y.H., 2015. Purple perilla extracts with alpha-asarone enhance cholesterol efflux from oxidized LDL-exposed macrophages. International journal of molecular medicine 35(4), 957-965. Peluso,

M.R.,

2006.

Flavonoids

attenuate

cardiovascular

disease,

inhibit

phosphodiesterase, and modulate lipid homeostasis in adipose tissue and liver. Exp Biol Med (Maywood) 231(8), 1287-1299. Peng, F., Du, Q., Peng, C., Wang, N., Tang, H., Xie, X., Shen, J., Chen, J., 2015. A Review: The Pharmacology of Isoliquiritigenin. Phytother Res 29(7), 969-977. Peterson, J., Dwyer, J., Adlercreutz, H., Scalbert, A., Jacques, P., McCullough, M.L., 2010. Dietary lignans: physiology and potential for cardiovascular disease risk reduction. Nutrition reviews 68(10), 571-603. Pferschy-Wenzig, E.M., Atanasov, A.G., Malainer, C., Noha, S.M., Kunert, O., Schuster, D., Heiss, E.H., Oberlies, N.H., Wagner, H., Bauer, R., Dirsch, V.M., 2014. Identification of isosilybin a from milk thistle seeds as an agonist of peroxisome proliferator-activated receptor gamma. J Nat Prod 77(4), 842-847. Phillips, M.C., 2014. Molecular mechanisms of cellular cholesterol efflux. The Journal of biological chemistry 289(35), 24020-24029. Polyak, S.J., Ferenci, P., Pawlotsky, J.M., 2013. Hepatoprotective and antiviral functions of silymarin components in hepatitis C virus infection. Hepatology (Baltimore, Md.) 57(3), 1262-1271. Post-White, J., Ladas, E.J., Kelly, K.M., 2007. Advances in the use of milk thistle (Silybum marianum). Integrative cancer therapies 6(2), 104-109. 59

Qian, H., Zhao, X., Cao, P., Lei, J., Yan, N., Gong, X., 2017. Structure of the Human Lipid Exporter ABCA1. Cell 169(7), 1228-1239 e1210. Quazi, F., Molday, R.S., 2013. Differential phospholipid substrates and directional transport by ATP-binding cassette proteins ABCA1, ABCA7, and ABCA4 and disease-causing mutants. The Journal of biological chemistry 288(48), 34414-34426. Ramirez, C.M., Lin, C.S., Abdelmohsen, K., Goedeke, L., Yoon, J.H., Madrigal-Matute, J., Martin-Ventura, J.L., Vo, D.T., Uren, P.J., Penalva, L.O., Gorospe, M., Fernandez-Hernando, C., 2014. RNA binding protein HuR regulates the expression of ABCA1. J Lipid Res 55(6), 1066-1076. Rayner, K.J., Suarez, Y., Davalos, A., Parathath, S., Fitzgerald, M.L., Tamehiro, N., Fisher, E.A., Moore, K.J., Fernandez-Hernando, C., 2010. MiR-33 contributes to the regulation of cholesterol homeostasis. Science 328(5985), 1570-1573. Rehman, M.U., Tahir, M., Khan, A.Q., Khan, R., Lateef, A., Oday, O.H., Qamar, W., Ali, F., Sultana, S., 2013. Chrysin suppresses renal carcinogenesis via amelioration of hyperproliferation, oxidative stress and inflammation: plausible role of NF-kappaB. Toxicol Lett 216(2-3), 146-158. Saenz, J., Alba, G., Reyes-Quiroz, M.E., Geniz, I., Jimenez, J., Sobrino, F., Santa-Maria, C., 2018a. Curcumin enhances LXRalpha in an AMP-activated protein kinase-dependent manner in human macrophages. J Nutr Biochem 54, 48-56. Saenz, J., Santa-Maria, C., Reyes-Quiroz, M.E., Geniz, I., Jimenez, J., Sobrino, F., Alba, G., 2018b. Grapefruit Flavonoid Naringenin Regulates the Expression of LXRalpha in THP-1 Macrophages by Modulating AMP-Activated Protein Kinase. Mol Pharm 15(5), 1735-1745. Sallam, T., Jones, M., Thomas, B.J., Wu, X., Gilliland, T., Qian, K., Eskin, A., Casero, D., Zhang, Z., Sandhu, J., Salisbury, D., Rajbhandari, P., Civelek, M., Hong, C., Ito, A., Liu, X., Daniel, B., Lusis, A.J., Whitelegge, J., Nagy, L., Castrillo, A., Smale, S., Tontonoz, P., 2018. Transcriptional regulation of macrophage cholesterol efflux and atherogenesis by a long noncoding RNA. Nat Med 24(3), 304-312. Santos, F.A., Rao, V.S., 2001. 1,8-cineol, a food flavoring agent, prevents ethanol-induced gastric injury in rats. Dig Dis Sci 46(2), 331-337. 60

Sarris, J., McIntyre, E., Camfield, D.A., 2013. Plant-based medicines for anxiety disorders, part 2: a review of clinical studies with supporting preclinical evidence. CNS Drugs 27(4), 301-319. Sarver, A.L., Li, L., Subramanian, S., 2010. MicroRNA miR-183 Functions as an Oncogene by Targeting the Transcription Factor EGR1 and Promoting Tumor Cell Migration. Cancer Research 70(23), 9570. Schwartz, K., Lawn, R.M., Wade, D.P., 2000. ABC1 gene expression and ApoA-I-mediated cholesterol efflux are regulated by LXR. Biochemical and biophysical research communications 274(3), 794-802. Sevov, M., Elfineh, L., Cavelier, L.B., 2006. Resveratrol regulates the expression of LXR-alpha in human macrophages. Biochemical and biophysical research communications 348(3), 1047-1054. Shara, M., Stohs, S.J., 2015. Efficacy and Safety of White Willow Bark (Salix alba) Extracts. Phytother Res 29(8), 1112-1116. Shen, G., Hebbar, V., Nair, S., Xu, C., Li, W., Lin, W., Keum, Y.S., Han, J., Gallo, M.A., Kong, A.N., 2004. Regulation of Nrf2 transactivation domain activity. The differential effects of mitogen-activated protein kinase cascades and synergistic stimulatory effect of Raf and CREB-binding protein. The Journal of biological chemistry 279(22), 23052-23060. Shoji, N., Umeyama, A., Takemoto, T., Kajiwara, A., Ohizumi, Y., 1986. Isolation of evodiamine, a powerful cardiotonic principle, from Evodia rutaecarpa Bentham (Rutaceae). J Pharm Sci 75(6), 612-613. Shukla, Y., Singh, M., 2007. Cancer preventive properties of ginger: a brief review. Food Chem Toxicol 45(5), 683-690. Skottova, N., Krecman, V., 1998. Silymarin as a potential hypocholesterolaemic drug. Physiol Res 47(1), 1-7. Smeriglio, A., Barreca, D., Bellocco, E., Trombetta, D., 2017. Proanthocyanidins and hydrolysable tannins: occurrence, dietary intake and pharmacological effects. Br J Pharmacol 174(11), 1244-1262. Smith, B., Land, H., 2012. Anticancer activity of the cholesterol exporter ABCA1 gene. 61

Cell Rep 2(3), 580-590. Song, C., Kokontis, J.M., Hiipakka, R.A., Liao, S., 1994. Ubiquitous receptor: a receptor that modulates gene activation by retinoic acid and thyroid hormone receptors. Proceedings of the National Academy of Sciences of the United States of America 91(23), 10809-10813. Soprano, D.R., Qin, P., Soprano, K.J., 2004. Retinoic acid receptors and cancers. Annu Rev Nutr 24, 201-221. Srinivasan, K., 2007. Black pepper and its pungent principle-piperine: a review of diverse physiological effects. Crit Rev Food Sci Nutr 47(8), 735-748. Sun, G.P., Wan, X., Xu, S.P., Wang, H., Liu, S.H., Wang, Z.G., 2008. Antiproliferation and apoptosis induction of paeonol in human esophageal cancer cell lines. Dis Esophagus 21(8), 723-729. Sun, L., Li, E., Wang, F., Wang, T., Qin, Z., Niu, S., Qiu, C., 2015. Quercetin increases macrophage cholesterol efflux to inhibit foam cell formation through activating PPARgamma-ABCA1 pathway. Int J Clin Exp Pathol 8(9), 10854-10860. Takahashi, K., Azuma, Y., Kobayashi, S., Azuma, J., Takahashi, K., Schaffer, S.W., Hattori, M., Namba, T., 2009. Tool from Traditional Medicines is Useful for Health-Medication: Bezoar Bovis and Taurine, in: Azuma, J., Schaffer, S.W., Ito, T. (Eds.), Taurine 7. Springer New York, New York, NY, pp. 95-103. Tang, W., Eisenbrand, G., 1992. Evodia rutaecarpa (Juss.) Benth, in: Tang, W., Eisenbrand, G. (Eds.), Chinese Drugs of Plant Origin: Chemistry, Pharmacology, and Use in Traditional and Modern Medicine. Springer Berlin Heidelberg, Berlin, Heidelberg, pp. 509-514. Tang, Y., Wu, H., Shao, B., Wang, Y., Liu, C., Guo, M., 2018. Celosins inhibit atherosclerosis in ApoE(-/-) mice and promote autophagy flow. J Ethnopharmacol 215, 74-82. Tauchen, J., Kokoska, L., 2017. The chemistry and pharmacology of Edelweiss: a review. Phytochemistry Reviews 16(2), 295-308. Terra, X., Fernandez-Larrea, J., Pujadas, G., Ardevol, A., Blade, C., Salvado, J., Arola, L., Blay, M., 2009. Inhibitory effects of grape seed procyanidins on foam cell formation 62

in vitro. Journal of agricultural and food chemistry 57(6), 2588-2594. Tovchiga, O.V., 2016. The influence of goutweed (Aegopodium podagraria L.) tincture and metformin on the carbohydrate and lipid metabolism in dexamethasone-treated rats. BMC Complement Altern Med 16, 235. Uto-Kondo, H., Ayaori, M., Nakaya, K., Takiguchi, S., Yakushiji, E., Ogura, M., Terao, Y., Ozasa, H., Sasaki, M., Komatsu, T., Sotherden, G.M., Hosoai, T., Sakurada, M., Ikewaki, K., 2014. Citrulline increases cholesterol efflux from macrophages in vitro and ex vivo via ATP-binding cassette transporters. J Clin Biochem Nutr 55(1), 32-39. van Breemen, R.B., Pajkovic, N., 2008. Multitargeted therapy of cancer by lycopene. Cancer Lett 269(2), 339-351. Voloshyna, I., Hai, O., Littlefield, M.J., Carsons, S., Reiss, A.B., 2013. Resveratrol mediates anti-atherogenic effects on cholesterol flux in human macrophages and endothelium via PPARgamma and adenosine. European journal of pharmacology 698(1-3), 299-309. Von Eckardstein, A., Langer, C., Engel, T., Schaukal, I., Cignarella, A., Reinhardt, J., Lorkowski, S., Li, Z., Zhou, X., Cullen, P., Assmann, G., 2001. ATP binding cassette transporter ABCA1 modulates the secretion of apolipoprotein E from human monocyte-derived macrophages. FASEB J 15(9), 1555-1561. Wagner, H., Bauer, R., Melchart, D., Xiao, P.-G., Staudinger, A., 2011. Fructus Evodiae Wuzhuyu, in: Wagner, H., Bauer, R., Melchart, D., Xiao, P.-G., Staudinger, A. (Eds.), Chromatographic Fingerprint Analysis of Herbal Medicines: Thin-layer and High Performance Liquid Chromatography of Chinese Drugs. Springer Vienna, Vienna, pp. 391-401. Wagsater, D., Dimberg, J., Sirsjo, A., 2003. Induction of ATP-binding cassette A1 by all-trans retinoic acid: possible role of liver X receptor-alpha. International journal of molecular medicine 11(4), 419-423. Wallace, T.C., 2011. Anthocyanins in cardiovascular disease. Adv Nutr 2(1), 1-7. Wang, B., Tontonoz, P., 2018. Liver X receptors in lipid signalling and membrane homeostasis. Nature reviews. Endocrinology 14(8), 452-463. Wang, C., Niimi, M., Watanabe, T., Wang, Y., Liang, J., Fan, J., 2018. Treatment of 63

atherosclerosis by traditional Chinese medicine: Questions and quandaries. Atherosclerosis 277, 136-144. Wang, D., Hiebl, V., Ladurner, A., Latkolik, S.L., Bucar, F., Heiss, E.H., Dirsch, V.M., Atanasov, A.G., 2018a. 6-Dihydroparadol, a Ginger Constituent, Enhances Cholesterol Efflux from THP-1-Derived Macrophages. Mol Nutr Food Res, e1800011. Wang, D., Ozen, C., Abu-Reidah, I.M., Chigurupati, S., Patra, J.K., Horbanczuk, J.O., Jozwik, A., Tzvetkov, N.T., Uhrin, P., Atanasov, A.G., 2018b. Vasculoprotective Effects of Pomegranate (Punica granatum L.). Frontiers in pharmacology 9, 544. Wang, D., Xia, M., Yan, X., Li, D., Wang, L., Xu, Y., Jin, T., Ling, W., 2012. Gut microbiota metabolism of anthocyanin promotes reverse cholesterol transport in mice via repressing miRNA-10b. Circulation research 111(8), 967-981. Wang, J., Ke, W., Bao, R., Hu, X., Chen, F., 2017. Beneficial effects of ginger Zingiber officinale Roscoe on obesity and metabolic syndrome: a review. Ann N Y Acad Sci 1398(1), 83-98. Wang, J.H., Keisala, T., Solakivi, T., Minasyan, A., Kalueff, A.V., Tuohimaa, P., 2009. Serum cholesterol and expression of ApoAI, LXRbeta and SREBP2 in vitamin D receptor knock-out mice. J Steroid Biochem Mol Biol 113(3-5), 222-226. Wang, L., Eftekhari, P., Schachner, D., Ignatova, I.D., Palme, V., Schilcher, N., Ladurner, A., Heiss, E.H., Stangl, H., Dirsch, V.M., Atanasov, A.G., 2018. Novel interactomics approach identifies ABCA1 as direct target of evodiamine, which increases macrophage cholesterol efflux. Sci Rep 8(1), 11061. Wang, L., Ladurner, A., Latkolik, S., Schwaiger, S., Linder, T., Hošek, J., Palme, V., Schilcher, N., Polanský, O., Heiss, E.H., Stangl, H., Mihovilovic, M.D., Stuppner, H., Dirsch, V.M., Atanasov, A.G., 2016. Leoligin, the Major Lignan from Edelweiss (Leontopodium nivale subsp. alpinum), Promotes Cholesterol Efflux from THP-1 Macrophages. Journal of Natural Products 79(6), 1651-1657. Wang, L., Palme, V., Rotter, S., Schilcher, N., Cukaj, M., Wang, D., Ladurner, A., Heiss, E.H., Stangl, H., Dirsch, V.M., Atanasov, A.G., 2017a. Piperine inhibits ABCA1 degradation and promotes cholesterol efflux from THP-1-derived macrophages. Mol Nutr Food Res 61(4). 64

Wang, L., Palme, V., Schilcher, N., Ladurner, A., Heiss, E.H., Stangl, H., Bauer, R., Dirsch, V.M., Atanasov, A.G., 2017b. The Dietary Constituent Falcarindiol Promotes Cholesterol Efflux from THP-1 Macrophages by Increasing ABCA1 Gene Transcription and Protein Stability. Frontiers in pharmacology 8, 596. Wang, L., Rotter, S., Ladurner, A., Heiss, E.H., Oberlies, N.H., Dirsch, V.M., Atanasov, A.G., 2015. Silymarin Constituents Enhance ABCA1 Expression in THP-1 Macrophages. Molecules 21(1), E55. Wang, L., Wesemann, S., Krenn, L., Ladurner, A., Heiss, E.H., Dirsch, V.M., Atanasov, A.G., 2017c. Erythrodiol, an Olive Oil Constituent, Increases the Half-Life of ABCA1 and Enhances Cholesterol Efflux from THP-1-Derived Macrophages. Frontiers in pharmacology 8, 375. Wang, N., Chen, W., Linsel-Nitschke, P., Martinez, L.O., Agerholm-Larsen, B., Silver, D.L., Tall, A.R., 2003. A PEST sequence in ABCA1 regulates degradation by calpain protease and stabilization of ABCA1 by apoA-I. J Clin Invest 111(1), 99-107. Wang, N., Tall, A.R., 2003. Regulation and mechanisms of ATP-binding cassette transporter A1-mediated cellular cholesterol efflux. Arterioscler Thromb Vasc Biol 23(7), 1178-1184. Wang, S., Zhang, X., Li, X., Liu, Q., Zhou, Y., Guo, P., Dong, Z., Wu, C., 2019. Phenylpropanoid glucosides from Tadehagi triquetrum inhibit oxLDL-evoked foam cell formation through modulating cholesterol homeostasis in RAW264.7 macrophages. Nat Prod Res 33(6), 893-896. Wang, S., Zhang, X., Liu, M., Luan, H., Ji, Y., Guo, P., Wu, C., 2015. Chrysin inhibits foam

cell formation through promoting

cholesterol efflux from RAW264.7

macrophages. Pharmaceutical biology 53(10), 1481-1487. Wang, X., Zhang, H., Chen, L., Shan, L., Fan, G., Gao, X., 2013. Liquorice, a unique "guide drug" of traditional Chinese medicine: a review of its role in drug interactions. J Ethnopharmacol 150(3), 781-790. Wang, Y., Oram, J.F., 2005. Unsaturated fatty acids phosphorylate and destabilize ABCA1 through a phospholipase D2 pathway. The Journal of biological chemistry 280(43), 35896-35903. 65

Wang, Y., Oram, J.F., 2007. Unsaturated fatty acids phosphorylate and destabilize ABCA1 through a protein kinase C delta pathway. J Lipid Res 48(5), 1062-1068. Wang, Y.F., Yang, X.F., Cheng, B., Mei, C.L., Li, Q.X., Xiao, H., Zeng, Q.T., Liao, Y.H., Liu, K., 2010. Protective effect of Astragalus polysaccharides on ATP binding cassette transporter A1 in THP-1 derived foam cells exposed to tumor necrosis factor-alpha. Phytother Res 24(3), 393-398. Wei, J., Ching, L.C., Zhao, J.F., Shyue, S.K., Lee, H.F., Kou, Y.R., Lee, T.S., 2013. Essential role of transient receptor potential vanilloid type 1 in evodiamine-mediated protection against atherosclerosis. Acta Physiol (Oxf) 207(2), 299-307. Wei, Z., Wang, J., Shi, M., Liu, W., Yang, Z., Fu, Y., 2016. Saikosaponin a inhibits LPS-induced inflammatory response by inducing liver X receptor alpha activation in primary mouse macrophages. Oncotarget 7(31), 48995-49007. Williamson, G., Clifford, M.N., 2010. Colonic metabolites of berry polyphenols: the missing link to biological activity? Br J Nutr 104 Suppl 3, S48-66. Woods, A., Vertommen, D., Neumann, D., Turk, R., Bayliss, J., Schlattner, U., Wallimann, T., Carling, D., Rider, M.H., 2003. Identification of phosphorylation sites in AMP-activated protein kinase (AMPK) for upstream AMPK kinases and study of their roles by site-directed mutagenesis. The Journal of biological chemistry 278(31), 28434-28442. Wu, C., Luan, H., Zhang, X., Wang, S., Zhang, X., Sun, X., Guo, P., 2014. Chlorogenic acid protects against atherosclerosis in ApoE-/- mice and promotes cholesterol efflux from RAW264.7 macrophages. PLoS One 9(9), e95452. Wu, M., Liu, M., Guo, G., Zhang, W., Liu, L., 2015. Polydatin Inhibits Formation of Macrophage-Derived Foam Cells. Evid Based Complement Alternat Med 2015, 729017. Xia, M., Hou, M., Zhu, H., Ma, J., Tang, Z., Wang, Q., Li, Y., Chi, D., Yu, X., Zhao, T., Han, P., Xia, X., Ling, W., 2005. Anthocyanins induce cholesterol efflux from mouse peritoneal macrophages: the role of the peroxisome proliferator-activated receptor {gamma}-liver X receptor {alpha}-ABCA1 pathway. The Journal of biological chemistry 280(44), 36792-36801. 66

Xie, C., Kang, J., Chen, J.R., Nagarajan, S., Badger, T.M., Wu, X., 2011. Phenolic acids are in vivo atheroprotective compounds appearing in the serum of rats after blueberry consumption. Journal of agricultural and food chemistry 59(18), 10381-10387. Xiong, J., Wang, K., Yuan, C., Xing, R., Ni, J., Hu, G., Chen, F., Wang, X., 2017. Luteolin protects mice from severe acute pancreatitis by exerting HO-1-mediated anti-inflammatory and antioxidant effects. International journal of molecular medicine 39(1), 113-125. Xu, S., Liu, P., 2013. Tanshinone II-A: new perspectives for old remedies. Expert opinion on therapeutic patents 23(2), 149-153. Xu, X., Li, Q., Pang, L., Huang, G., Huang, J., Shi, M., Sun, X., Wang, Y., 2013. Arctigenin

promotes

cholesterol

efflux

from

THP-1

macrophages

through

PPAR-gamma/LXR-alpha signaling pathway. Biochemical and biophysical research communications 441(2), 321-326. Xu, Y., Liu, Q., Xu, Y., Liu, C., Wang, X., He, X., Zhu, N., Liu, J., Wu, Y., Li, Y., Li, N., Feng, T., Lai, F., Zhang, M., Hong, B., Jiang, J.D., Si, S., 2014. Rutaecarpine suppresses atherosclerosis in ApoE-/- mice through upregulating ABCA1 and SR-BI within RCT. J Lipid Res 55(8), 1634-1647. Yamaki, M., Kato, T., Kashihara, M., Takagi, S., 1990. Isoflavones of Belamcanda chinensis. Planta Med 56(3), 335. Yamauchi, Y., Hayashi, M., Abe-Dohmae, S., Yokoyama, S., 2003. Apolipoprotein A-I activates protein kinase C alpha signaling to phosphorylate and stabilize ATP binding cassette transporter A1 for the high density lipoprotein assembly. The Journal of biological chemistry 278(48), 47890-47897. Yamori, Y., Liu, L., Ikeda, K., Miura, A., Mizushima, S., Miki, T., Nara, Y., Disease, W.H.-C., Alimentary Comprarison Study, G., 2001. Distribution of twenty-four hour urinary taurine excretion and association with ischemic heart disease mortality in 24 populations of 16 countries: results from the WHO-CARDIAC study. Hypertens Res 24(4), 453-457. Yang, C.M., Lu, I.H., Chen, H.Y., Hu, M.L., 2012a. Lycopene inhibits the proliferation 67

of

androgen-dependent human prostate tumor cells through activation of

PPARgamma-LXRalpha-ABCA1 pathway. J Nutr Biochem 23(1), 8-17. Yang, C.M., Lu, Y.L., Chen, H.Y., Hu, M.L., 2012b. Lycopene and the LXRalpha agonist T0901317 synergistically inhibit the proliferation of androgen-independent prostate cancer cells via the PPARgamma-LXRalpha-ABCA1 pathway. J Nutr Biochem 23(9), 1155-1162. Yang, F., Dong, X., Yin, X., Wang, W., You, L., Ni, J., 2017. Radix Bupleuri: A Review of Traditional Uses, Botany, Phytochemistry, Pharmacology, and Toxicology. Biomed Res Int 2017, 7597596. Yang, Y., Li, X., Peng, L., An, L., Sun, N., Hu, X., Zhou, P., Xu, Y., Li, P., Chen, J., 2018. Tanshindiol C inhibits oxidized low-density lipoprotein induced macrophage foam cell formation via a peroxiredoxin 1 dependent pathway. Biochim Biophys Acta Mol Basis Dis 1864(3), 882-890. Yin, K., You, Y., Swier, V., Tang, L., Radwan, M.M., Pandya, A.N., Agrawal, D.K., 2015. Vitamin D Protects Against Atherosclerosis via Regulation of Cholesterol Efflux and Macrophage Polarization in Hypercholesterolemic Swine. Arterioscler Thromb Vasc Biol 35(11), 2432-2442. Yokoyama, S., 2006. Assembly of high-density lipoprotein. Arterioscler Thromb Vasc Biol 26(1), 20-27. Yokoyama, S., Arakawa, R., Wu, C.A., Iwamoto, N., Lu, R., Tsujita, M., Abe-Dohmae, S., 2012. Calpain-mediated ABCA1 degradation: post-translational regulation of ABCA1 for HDL biogenesis. Biochim Biophys Acta 1821(3), 547-551. Yu, R., Lv, Y., Wang, J., Pan, N., Zhang, R., Wang, X., Yu, H., Tan, L., Zhao, Y., Li, B., 2016. Baicalin promotes cholesterol efflux by regulating the expression of SR-BI in macrophages. Exp Ther Med 12(6), 4113-4120. Yue, J., Li, B., Jing, Q., Guan, Q., 2015. Salvianolic acid B accelerated ABCA1-dependent cholesterol efflux by targeting PPAR-gamma and LXRalpha. Biochemical and biophysical research communications 462(3), 233-238. Zang, W., Bian, H., Huang, X., Yin, G., Zhang, C., Han, L.I., Hao, P., Ding, S., Sun, Y.U., Yang, Z., Hoffman, R.M., Tang, D., 2019. Traditional Chinese Medicine (TCM) 68

Astragalus Membranaceus and Curcuma Wenyujin Promote Vascular Normalization in Tumor-derived Endothelial Cells of Human Hepatocellular Carcinoma. Anticancer Res 39(6), 2739-2747. Zarubica, A., Trompier, D., Chimini, G., 2007. ABCA1, from pathology to membrane function. Pflugers Arch 453(5), 569-579. Zhang, B.C., Zhang, C.W., Wang, C., Pan, D.F., Xu, T.D., Li, D.Y., 2016. Luteolin Attenuates Foam Cell Formation and Apoptosis in Ox-LDL-Stimulated Macrophages by Enhancing Autophagy. Cell Physiol Biochem 39(5), 2065-2076. Zhang, H., Cui, J., Tian, G., DiMarco-Crook, C., Gao, W., Zhao, C., Li, G., Lian, Y., Xiao, H., Zheng, J., 2019. Efficiency of four different dietary preparation methods in extracting functional compounds from dried tangerine peel. Food Chem 289, 340-350. Zhang, Y., Guo, W., Wen, Y., Xiong, Q., Liu, H., Wu, J., Zou, Y., Zhu, Y., 2012. SCM-198 attenuates early atherosclerotic lesions in hypercholesterolemic rabbits via modulation of the inflammatory and oxidative stress pathways. Atherosclerosis 224(1), 43-50. Zhang, Z., Lam, T.N., Zuo, Z., 2013. Radix Puerariae: an overview of its chemistry, pharmacology, pharmacokinetics, and clinical use. J Clin Pharmacol 53(8), 787-811. Zhao, G.J., Tang, S.L., Lv, Y.C., Ouyang, X.P., He, P.P., Yao, F., Chen, W.J., Lu, Q., Tang, Y.Y., Zhang, M., Fu, Y., Zhang, D.W., Yin, K., Tang, C.K., 2013. Antagonism of betulinic acid on LPS-mediated inhibition of ABCA1 and cholesterol efflux through inhibiting nuclear factor-kappaB signaling pathway and miR-33 expression. PLoS One 8(9), e74782. Zhao, J.F., Ching, L.C., Huang, Y.C., Chen, C.Y., Chiang, A.N., Kou, Y.R., Shyue, S.K., Lee, T.S., 2012. Molecular mechanism of curcumin on the suppression of cholesterol accumulation in macrophage foam cells and atherosclerosis. Mol Nutr Food Res 56(5), 691-701. Zhao, J.F., Jim Leu, S.J., Shyue, S.K., Su, K.H., Wei, J., Lee, T.S., 2013. Novel effect of paeonol on the formation of foam cells: promotion of LXRalpha-ABCA1-dependent cholesterol efflux in macrophages. Am J Chin Med 41(5), 1079-1096. Zhao, Q., Chen, X.Y., Martin, C., 2016. Scutellaria baicalensis, the golden herb from 69

the garden of Chinese medicinal plants. Sci Bull (Beijing) 61(18), 1391-1398. Zhao, S., Li, J., Wang, L., Wu, X., 2016. Pomegranate peel polyphenols inhibit lipid accumulation and enhance cholesterol efflux in raw264.7 macrophages. Food Funct 7(7), 3201-3210. Zhao, W., Haller, V., Ritsch, A., 2015. The polyphenol PGG enhances expression of SR-BI and ABCA1 in J774 and THP-1 macrophages. Atherosclerosis 242(2), 611-617. Zhao, Y., Li, H., Gao, Z., Xu, H., 2005. Effects of dietary baicalin supplementation on iron overload-induced mouse liver oxidative injury. European journal of pharmacology 509(2-3), 195-200. Zhou, L., Zuo, Z., Chow, M.S., 2005. Danshen: an overview of its chemistry, pharmacology, pharmacokinetics, and clinical use. J Clin Pharmacol 45(12), 1345-1359. Zhou, W., Lin, J., Chen, H., Wang, J., Liu, Y., Xia, M., 2015. Retinoic acid induces macrophage cholesterol efflux and inhibits atherosclerotic plaque formation in apoE-deficient mice. Br J Nutr 114(4), 509-518. Zhou, X., Engel, T., Goepfert, C., Erren, M., Assmann, G., von Eckardstein, A., 2002. The ATP binding cassette transporter A1 contributes to the secretion of interleukin 1beta from macrophages but not from monocytes. Biochemical and biophysical research communications 291(3), 598-604. Zhou, X., Li, Z.C., Chen, P.P., Xie, R.F., 2019. Primary Mechanism Study of Panax notoginseng Flower (Herb) on Myocardial Infarction in Rats. Cardiol Res Pract 2019, 8723076. Zhou, Y., Chen, R., Liu, D., Wu, C., Guo, P., Lin, W., 2017. Asperlin Inhibits LPS-Evoked Foam Cell Formation and Prevents Atherosclerosis in ApoE(-/-) Mice. Mar Drugs 15(11). Zhu, S., Liu, J.H., 2015. Zerumbone, A Natural Cyclic Sesquiterpene, Promotes ABCA1-Dependent

Cholesterol

Efflux

from

Human

THP-1

Macrophages.

Pharmacology 95(5-6), 258-263. Zolberg Relevy, N., Bechor, S., Harari, A., Ben-Amotz, A., Kamari, Y., Harats, D., 70

Shaish, A., 2015. The inhibition of macrophage foam cell formation by 9-cis beta-carotene is driven by BCMO1 activity. PLoS One 10(1), e0115272. Zschocke, S., Lehner, M., Bauer, R., 1997. 5-Lipoxygenase and cyclooxygenase inhibitory active constituents from Qianghuo (Notopterygium incisum). Planta Med 63(3), 203-206.

71

Table 1. Compounds increasing ABCA1 mRNA and/or protein expression. The table shows the test system, the concentration(s) investigated, the major effects mediated and/or the targets found to be influenced.

Compound

Test system

Concentration

Effects/Targets

Reference

Alpinetin

oxLDL-loaded

50 – 150 µg/ml

ABCA1 mRNA and

(Jiang et al.,

THP-1

protein ↑, PPARγ and

2015)

macrophages,

LXRα mRNA and

oxLDL-loaded

protein ↑

HMDMs Anthocyanins:

MPMs and/or

Cyanidin-3-O-βglucoside,

1 – 100 µM

ABCA1 mRNA and

(Xia et al.,

acLDL-loaded

protein ↑,

2005)

MPMs

transcriptional activity

Peonidin-3-O-β-

of LXR and PPARγ ↑,

glucoside

LXRα and PPARγ mRNA ↑

Baicalin

YPEN-1 rat

1 – 10 µM

endothelial cells

Activation of PPARγ,

(Lim et al.,

PPARγ protein ↑

2012)

New Zealand

224 µmol/kg for

size of atherosclerotic

(He, X.W. et

rabbits on a high-

8 weeks

lesions ↓, lipid

al., 2016)

fat diet

accumulation in carotid arteries ↓, total and LDL cholesterol ↓

oxLDL-loaded

50 and 100 µM

ABCA1 mRNA and

THP-1

protein ↑, PPARγ and

macrophages

LXRα mRNA and protein ↑

oxLDL-loaded

50 µM

THP-1

PPARγ and LXRα

(Yu et al.,

protein ↑

2016)

activation of PPARγ

(Feng et al.,

macrophages Chrysin

HEK293T cells

not given

2014) oxLDL-treated RAW264.7

10 µM

ABCA1 mRNA ↑,

(Wang, S. et

activation of PPARγ,

al., 2015)

macrophages

PPARγ and LXRα mRNA ↑

Hesperetin

Sprague-Dawley

100 mg/kg/day

rats on a high-

for 6 weeks

plasma cholesterol ↓

(Lee et al., 1999)

cholesterol diet THP-1

5 – 15 µM

macrophages

ABCA1 mRNA and

(Iio et al.,

protein ↑, LXR

2012)

activation, PPARγ activation U-2OS

20 – 160 µM

PPARγ activation

osteosarcoma cells Iristectorigenin

HEK293 cells

(Liu et al., 2008)

5 – 20 µM

activation of LXRα and

(Jun et al.,

LXRβ

2012)

5 and 10 µM

ABCA1 mRNA ↑

25 – 100 µg/ml

ABCA1 mRNA and

(Li et al.,

THP-1

protein ↑, LXRα and

2017)

macrophages

PPARγ mRNA and

RAW264.7 macrophages Puerarin

oxLDL-loaded

protein ↑, phosphorylation of AMPK ↑, miRNA-7 ↓, liver kinase B1 mRNA and protein ↑ Silymarin:

THP-1

isosilybin A,

macrophages

10 µM

ABCA1 protein ↑

(Wang, L. et al., 2015)

silybin B, silychristin, isosilychristin, taxifolin Isosilybin A

HEK293 cells

30 µM

activation of PPARγ

(PferschyWenzig et al., 2014; Wang et al., 2014)

Wogonin

J774.A1

10 – 40 µM

macrophages

ABCA1 protein ↑,

(Chen et al.,

ABCA1 mRNA ↔,

2011)

phosphorylation of ABCA1 ↓ via increased interaction between ABCA1 and PP2B Luteolin

ABCA1 protein ↑

(Zhang et

RAW264.7

compared to oxLDL

al., 2016)

macrophages

only, activation of

oxLDL-loaded

25 µM

autophagy Kuwanon G

RAW264.7

20 µM

ABCA1 mRNA and

(Liu et al.,

macrophages

protein ↑, LXRα protein

2018)

and/or oxLDL-

↑, reversion of oxLDL

treated RAW264.7

induced increase in

macrophages

NF-ᴋB p65 phosphorylation and decrease in IᴋBα degradation

-/-

apoE mice on a

5 mg/kg every

total cholesterol and

high-fat diet

other day for 16

LDL cholesterol ↓,

weeks

lesion areas in the aortic sinus and lipid deposition in the atherosclerotic plaques ↓, reduced macrophage content in the lesion area

Quercetin

RAW264.7 macrophages

40 – 200 µM

ABCA1 mRNA and

(Chang et

protein ↑,

al., 2012)

phosphorylation of TAK1 ↑ -> phosphorylation of MKK3/6 ↑ -> phosphorylation of p38

↑ -> binding of Sp1 and LXRα to the promoter of ABCA1 facilitated THP-1

0.15 – 15 µM

macrophages

ABCA1 mRNA and

(Lee et al.,

protein ↑, PPARγ and

2013)

LXRα protein levels ↑ RAW264.7

2.5 µM

ABCA1 protein ↑

macrophages -/-

(Cui et al., 2017)

apoE mice on a

12.5 mg/kg/day

high-fat diet

for 8 weeks

oxLDL-loaded

20 µM

improvement of RCT

ABCA1 protein ↑, LXRα (Li, S. et al., protein ↑

2018)

ABCA1 mRNA and

(Sun et al.,

THP-1

protein ↑, PPARγ

2015)

macrophages

mRNA and protein ↑,

RAW264.7 macrophages oxLDL-loaded

25 – 200 µM

transcriptional activity of PPARγ ↑, LXRα mRNA and protein ↔ Naringenin

THP-1

100 µM

macrophages

ABCA1 mRNA, LXRα

(Saenz et

mRNA and protein ↑

al., 2018b)

via AMPK human neutrophils

100 µM

ABCA1 and LXRα mRNA ↑

RAW264.7

100 µM

ABCA1 mRNA ↑

0.6 µM

ABCA1 mRNA ↑

macrophages M1 macrophages, M2a macrophages Naringenin-7-O-

(Dall'Asta et al., 2013)

M1 macrophages

0.6 µM

ABCA1 mRNA ↑

MPMs treated with

0.1 µg/ml

ABCA1 and LXRα

(Du et al.,

mRNA ↑

2016)

glucuronide Isoliquiritigenin

LPS MPMs incubated with oxLDL

0.5 µg/ml

PPARγ protein ↑, ABCA1 protein ↑ in

comparison to untreated control but ↓ compared to without isoliquiritigenin apoE-/- mice on a

20 mg/kg/day or

total plasma

Western diet

100 mg/kg/day

cholesterol ↓, VLDL

for 12 weeks

and LDL cholesterol ↓, lesion area in the aortic roots ↓, ABCA1, PPARγ, CYP7A1 and CYP27A1 mRNA ↑ in livers

Curcumin

J774A.1 cells

5 – 40 µM

ABCA1 mRNA and

(Zhao et al.,

protein ↑, half-life of

2012)

ABCA1↑, LXRα activity and ABCA1 promoter activity ↑, implication of calmodulin -/-

apoE mice

20 mg/kg/day for ABCA1 protein 4 weeks

expression in aortas ↑, atherosclerotic lesions in aortic roots ↓, serum total cholesterol, triglycerides and nonHDL-cholesterol ↓, serum HDL cholesterol ↑

LPS and IFN-γ

6.25 and 12.5

ABCA1 and PPARγ

(Chen et al.,

treated RAW264.7

µM

protein ↑

2015)

10 – 20 µM

ABCA1 mRNA and

(Lin et al.,

protein ↑, LXRα mRNA

2015)

macrophages incubated with oxLDL oxLDL-loaded THP-1

and protein ↑, protein

macrophages

levels of p-AMPK and p-SIRT1 ↑ →AMPKSIRT1-LXRα pathway THP-1

5 µM

macrophages

ABCA1 mRNA ↑, LXRα

(Saenz et

mRNA and protein ↑,

al., 2018a)

protein level of pAMPK ↑ Asperlin

ABCA1 mRNA ↑,

(Zhou et al.,

RAW264.7

PPARγ mRNA and

2017)

macrophages

protein ↑

LPS-treated

0.1 – 10 µM

apoE-/- mice on a

80 mg/kg/day for formation of

high-cholesterol

12 weeks

in the aorta ↓

diet Emodin

oxLDL-loaded

atherosclerotic plaques

1 – 10 µM

ABCA1, PPARγ and

(Fu et al.,

THP-1

LXRα mRNA and

2014)

macrophages

protein ↑, involvement of PPARγ-LXRα signaling axis in ABCA1 protein ↑

Cineole

RAW264.7

50 and 100 µM

macrophages

ABCA1 mRNA and

(Jun et al.,

protein ↑, LXRα and

2013)

LXRβ mRNA and protein ↑ CHO-K1 cells

50 – 200 µM

LXRα and LXRβ transactivation ↑

HepG2 cells

50 and 100 µM

LXRα mRNA and protein, as well as expression of LXRαresponsive genes ↓

Zerumbone

THP-1 macrophages

10 – 100 µM

ABCA1 mRNA and

(Zhu and

protein ↑,

Liu, 2015)

phosphorylation of ERK1/2 ↑

Tanshinone IIA

THP-1

1 – 10 µM

ABCA1 mRNA ↑

macrophages THP-1

(Liu et al., 2014)

1 – 30 µM

ABCA1 protein ↑

1 – 30 µM

activation of the ERK-

macrophages, HMDMs THP-1 macrophages,

Nrf2-HO-1 pathway, as

some experiments

shown by ↑ ERK

also in other

phosphorylation, ↑ Nrf2

macrophages

phosphorylation and

(HMDMs and

nuclear translocation

MPMs)

and ↑ HO-1 protein amongst others

-/-

apoE mice on a

30 mg/kg/day for ABCA1 protein

high-cholesterol

12 weeks

diet

expression ↑ in the aortas, atherosclerotic plaque size ↓

macrophages from

10 mg/kg/day for ABCA1 mRNA and

Sprague-Dawley

8 weeks,

rats on a high-fat

supplied as

diet

sodium

protein ↑

(Jia et al., 2016)

tanshinone IIA sulfonate oxLDL-treated

10 µg/µl

ABCA1 mRNA and protein ↑

THP-1 macrophages Tanshindiol C

RAW264.7

1 – 10 µM

macrophages

ABCA1 mRNA and

(Yang et al.,

protein ↑, SIRT1, Nrf2

2018)

and prdx1 mRNA and protein ↑ Andrographolide

ABCA1 mRNA and

(Lin et al.,

J774A.1

protein ↑, nuclear

2018)

macrophages

translocation of LXRα

oxLDL-loaded

0.5 and 1 µM

and its DNA binding

activity ↑ Erythrodiol

THP-1

1 – 15 µM

macrophages

ABCA1 protein ↑ by

(Wang et

inhibiting its

al., 2017c)

degradation Betulinic acid

LPS-treated

0.5 – 2 µg/ml

ABCA1 mRNA and

(Zhao, G.J.

oxLDL-loaded

protein ↑, reduction of

et al., 2013)

THP-1

protein expression of

macrophages

nuclear NF-ᴋB p65, phosphorylated IᴋBα ↓ and phosphorylation of p65 ↓, downregulation of miRNA-33a/b

-/-

apoE mice

50 mg/kg/day for ABCA1 protein ↑ in the

treated with LPS

8 weeks

aorta, miRNA-33a

(2.5 mg/kg once

levels ↓, NF-ᴋB p65

per week)

protein ↓, triglycerides, total cholesterol and LDL cholesterol ↓, HDL cholesterol ↑

Betulin

THP-1

0.1 – 2.5 µg/ml

macrophages,

ABCA1 mRNA and

(Gui et al.,

protein ↑

2016)

RAW264.7 macrophages RAW264.7

0.1 – 2.5 µg/ml

macrophages

nuclear protein expression of SREBPs ↓ which can bind to Ebox motifs in the ABCA1 promoter

-/-

ABCA1 protein ↑ in the

apoE mice on a

20 and 40

high-fat diet

mg/kg/day for 12 aortic sinus, lesions in weeks

en face aortas and aortic sinuses ↓, plasma total and LDL cholesterol ↓, RCT ↑

Saikosaponin A

LPS-treated MPMs

3 – 12 µM

ABCA1 and LXRα

(Wei et al.,

protein level ↑

2016)

MPMs

3 – 12 µM

LXR transactivation ↑

oxLDL-loaded

50 µM

ABCA1 and PPARγ

(He, D. et

protein ↑

al., 2016)

ABCA1 and LXRα

(Jia et al.,

mRNA and protein ↑

2010)

ABCA1 mRNA ↑, LXRα

(Fan et al.,

mRNA ↑,

2012)

THP-1 macrophages Panax

oxLDL-loaded

notoginseng

alveolar

saponins

macrophages from

20 – 80 µg/ml

SD rats THP-1

25 – 100 µg/ml

macrophages

transcriptional activation of the LXRα gene promoter Wistar rats on a

100 mg/kg/day

less atherosclerotic

high-cholesterol

for 10 weeks

spots and streaks in

diet and zymosan

the aortas, LXRα

A treatment

mRNA and protein in aortas ↑

Celosins

oxLDL-treated

12.5 – 50 µg/ml

ABCA1 mRNA ↑

MPMs

(Tang et al., 2018)

apoE-/- mice on a

10 – 90 mg/kg

Smoother and smaller

high-fat diet

for 4 weeks

atherosclerotic plaques, number of autophagy bodies ↑, total cholesterol, triglycerides and LDLcholesterol ↓

Vitamin E

Male albino rabbits

50 mg/kg/day for reduced incidence of

(Bozaykut et

on a high-

4 weeks

al., 2014)

cholesterol diet

atherosclerotic lesions, PPARγ and ABCA1 mRNA ↑

Carotenoids:

-/-

apoE mice

20 mg/kg/day for ABCA1 protein

(Iizuka et

astaxanthin

4 weeks

expression in aortas ↑,

al., 2012)

atherosclerotic lesions

(Chen et al.,

in aortic roots ↓, serum

2015)

total cholesterol,

(Lin et al.,

triglycerides and non-

2015)

HDL-cholesterol ↓,

(Chen et al.,

serum HDL cholesterol

2015)

↑

(Lin et al., 2015) (Chen et al., 2015)

LPS and IFN-γ

6.25 and 12.5

ABCA1 and PPARγ

treated RAW264.7

µM

protein ↑

10 – 20 µM

ABCA1 mRNA and

(Lin et al., 2015)

macrophages incubated with oxLDL oxLDL-loaded THP-1

protein ↑, LXRα mRNA

macrophages

and protein ↑, protein levels of p-AMPK and p-SIRT1 ↑ →AMPKSIRT1-LXRα pathway

Carotenoids: 9-

THP-1

cis-β-carotene

macrophages

5 µM

ABCA1 mRNA ↑, LXRα

(Saenz et

mRNA and protein ↑,

al., 2018a)

protein level of pAMPK ↑

RAW264.7

2 µM

macrophages

ABCA1 mRNA and

(Bechor et

protein ↑, activation of

al., 2016)

RXR Carotenoids: all-

RAW264.7

2 µM

ABCA1 mRNA ↔,

trans-β-carotene

macrophages

Carotenoids: 9-

acLDL-loaded

cis retinoic acid

THP-1

ABCA1 protein ↑ 10 µM

ABCA1 protein ↑

(Kiss et al., 2005)

macrophages, acLDL-loaded J774 cells, acLDLloaded MPMs, acLDL-loaded HMDMs RAW264.7

10 µM

macrophages

increased transcription

(Schwartz et

from an 1.64 kb

al., 2000)

ABCA1 promoter via RXR, ABCA1 mRNA ↑ primary neurons,

10 µM

astrocytes and

ABCA1 mRNA and

(Koldamova

protein ↑

et al., 2003)

ABCA1 mRNA and

(Zhou et al.,

protein ↑, LXRα mRNA

2015)

microglia isolated from embryonic rat brain J774A.1

0.1 – 10 µM

macrophages

and protein ↑ HEK293T cells

0.1 – 10 µM

transcriptional activity of LXRE-Luc induced

-/-

apoE mice on a

2 mg/kg four to

atherosclerotic plaque

high-fat diet

five times per

lesion in the aortic

week for 8

sinus ↓, serum total

weeks

and LDL cholesterol ↓

MPMs from treated

2 mg/kg four to

ABCA1 protein ↑, LXRα

mice

five times per

protein ↑

week for 8 weeks Carotenoids: all-

MPMs

0.25 – 10 µM

ABCA1 mRNA and

(Costet et

trans retinoic

(protein), 0.1 – 5

protein ↑

al., 2003)

acid

µM (mRNA)

HMDMs

RAW264.7

10 µM (protein),

ABCA1 mRNA and

0.5 – 5 µM

protein ↑, LXRα mRNA

(mRNA)

↑

10 µM

ABCA1 protein ↑ via

(Manna et

activation of LXR

al., 2015)

macrophages

signaling THP-1

0.1 – 1000 nM

ABCA1 mRNA and

(Wagsater

macrophages

(mRNA), 1 µM

protein ↑, LXRα mRNA

et al., 2003)

(protein)

and protein ↑

0.5 – 2 µM

ABCA1 protein ↑,

(Palozza et

HMG-CoA reductase

al., 2011)

Carotenoids:

THP-1

lycopene

macrophages

protein ↓, RhoA inactivation and subsequent increase in PPARγ mRNA and protein and LXRα protein LNCaP cells,

Arctigenin

ABCA1 mRNA and

(Yang et al.,

DU145 cells, PC-3

protein ↑, PPARγ and

2012a;

cells

LXRα mRNA and

Yang et al.,

protein ↑

2012b)

ABCA1 mRNA and

(Xu et al.,

THP-1

protein ↑, LXRα and

2013)

macrophages

PPARγ mRNA and

oxLDL-loaded

2.5 – 20 µM

10 – 100 µM

protein ↑, knock-down of PPARγ or LXRα abolished induction of ABCA1 suggesting implication of PPARγ and LXRα Leoligin

THP-1 macrophages

10 µM

ABCA1 mRNA and

(Wang et

protein ↑, possibly

al., 2016)

transcriptional regulation, detailed

molecular mechanisms not yet elucidated Honokiol

ABCA1 mRNA and

(Jung et al.,

U251-MG cells

protein ↑, ABCA1

2010)

(human glioma)

promoter activity ↑

stably transfected

THP-1

0.1 – 20 µM

10 µM

protein ↑

macrophages cell-free assay

ABCA1 mRNA and

1 – 30 µM

ligand of RXRβ

not possible to

activation of RXRα

(time resolved fluorescence energy transfer) HEK293 cells

tell from the

(Kotani et al., 2010)

figures and not given in the text yeast

not possible to

binding to RXRα as

transformants

tell from the

shown by a two-hybrid

figures and not

assay

given in the text RAW264.7

1 – 20 µM

protein ↑

macrophages rat primary

ABCA1 mRNA and

10 mM

neurons, rat

ABCA1 mRNA and

(Jung et al.,

protein ↑

2010)

ABCA1 mRNA ↑, LXRα

(Sevov et

mRNA ↑

al., 2006)

primary astrocytes Resveratrol

THP-1

50 and 100 µM

macrophages, HMDMs THP-1

50 and 100 µM

Nuclear and cytosolic LXRα protein ↑, binding

macrophages

of RNA polymerase II to the LXRα promoter ↑ THP-1

10 and 25 µM

ABCA1mRNA and

(Voloshyna

macrophages and/

protein ↑, mRNA and

et al., 2013)

or HAEC and/or

protein of CYP27A1 ↑ -

HMDMs

> 27hydroxycholesterol synthesis -> LXR ligand, effects dependent on PPARγ and adenosine 2A receptor pathways

Polydatin

oxLDL-treated MPMs from apoE

8.9 µg/ml -/-

ABCA1 and PPARγ

(Wu et al.,

mRNA ↑

2015)

ABCA1 protein ↑

(Guo et al.,

mice Three new

RAW264.7

stilbenoids in

macrophages

1 µg/ml

2018)

Cannabis sativa f. sativa α-Asarone

oxLDL-loaded

1 – 10 µM

J774A.1

ABCA1 protein ↑,

(Park et al.,

RXRα mRNA ↑

2015)

ABCA1, LXRα and

(Wu et al.,

PPARγ mRNA ↑

2014)

macrophages Chorogenic acid

RAW264.7

not given

macrophages HEK293T

1 and 10 µM

PPARγ transactivation ↑

-/-

apoE mice on a

200 and 400

atherosclerotic lesion

high-fat diet

mg/kg for 12

area ↓, triglycerides,

weeks

total and LDL cholesterol ↓

HepG2 cells

chlorogenic

ABCA1 and CYP7A1

(Hao et al.,

acid-enriched

mRNA ↑, LXRα mRNA

2016)

extract from

↓ by chlorogenic acid

Eucommia

and ↔ by the extract

ulmoides leaves (25 mg/L) as well as chlorogenic acid (30 µM)

Salidroside

ABCA1 protein ↑, Nrf2

(Ni et al.,

macrophages pre-

protein ↑ at 0.1 and 1

2017)

treated with

µM, phosphorylation of

salidroside and

Akt ↑, phosphorylation

then incubated with

of JNK, ERK and p38

oxLDL

MAPK ↓

THP-1

0.1 – 10 µM

Phenylpropanoid oxLDL-treated

Three of seven

ABCA1 mRNA ↑, one

(Wang et

glucosides from

RAW264.7

glucosides

compound increased

al., 2019)

Tadehagi

macrophages

isolated, 10 µM

LXRα mRNA

triquetrum

expression

Salicylic acid

BMDMs from WT

(Salicylate)

and Ampk β1-/-

3 mM

mRNA level of LXRα

(Fullerton et

and ABCA1 ↑ in WT

al., 2015)

-/-

mice and acLDL-

but not in Ampk β1

loaded BMDMs

macrophages

from WT and Ampk

suggesting regulation

-/-

via AMPK

β1 mice Protocatechuic

acLDL-loaded

acid

0.25 – 1 µM

ABCA1 mRNA and

(Wang et

MPMs and THP-1

protein ↑,

al., 2012)

macrophages

downregulation of miRNA-10b

MPMs from apoE

-/-

mice on the AIN-

5 mg/kg/day for

ABCA1 mRNA and

2 weeks

protein ↑,

93G diet

downregulation of miRNA-10b

apoE-/- mice on the

5 mg/kg/day for

AIN-93G diet

2 weeks

-/-

Increased RCT

apoE mice on the

5 mg/kg/day for

Atherosclerotic lesion

AIN-93G diet

4 weeks

area in the aortic sinus and cholesterol content in the whole aorta ↓

Blueberry

RAW264.7

1x mixture

ABCA1 mRNA and

(Xie et al.,

phenolic

macrophages

contained:

protein ↑, inhibition of

2011)

hippuric acid, 3-

phosphorylation of

hydroxyphenyla

JNK, ERK1/2 and p38

compounds

cetic acid, 3-

MAPK induced by LPS

hydroxdybenzoi c acid, ferulic acid, 3-(3hydroxyphenyl)p ropionic acid, 3(4hydroxyphenyl)p ropionic acid, 3hydroxycinnamic acid Danshensu (3-

oxLDL-loaded

(3,4dihydroxyphenyl

0.1 – 10 µM

ABCA1 mRNA and

(Gao et al.,

RAW264.7

protein ↑, PPARγ and

2016)

macrophages

LXRα mRNA ↑, PPARγ protein ↑

)-2hydroxypropanoi c acid) Salvianolic acid

THP-1

B

macrophages

0.1 – 10 µM

ABCA1 mRNA and

(Yue et al.,

protein ↑, PPARγ and

2015)

LXRα protein ↑ Ellagic acid

Pomegranate

ABCA1 mRNA and

(Park et al.,

J774A.1

protein ↑, PPARγ and

2011)

macrophages

LXRα protein ↑

oxLDL-loaded

RAW264.7

1 – 5 µM

5 – 50 µg/ml

peel polyphenols macrophages

ABCA1, LXRα and

(Zhao et al.,

PPARγ mRNA ↑,

2016)

ABCA1 and LXRα protein expression ↑ 1,2,3,4,6-penta-

THP-1

O-galloyl-β-ᴅ-

macrophages,

glucose

J774 cells, oxLDLloaded THP-1 macrophages, oxLDL-loaded J774 cells

0.1 – 10 µM

ABCA1 protein ↑

(Zhao et al., 2015)

↓ TNF-α-induced

(Jiang et al.,

THP-1

downregulation of

2012)

macrophages

ABCA1, diminished

treated with TNF-α

inhibitory effect of TNF-

Epigallocatechin

oxLDL-loaded

-3-gallate

40 µg/ml

α on the activity of the ABCA1 promoter, inhibition of the effects of TNF-α on ABCA1 via inhibiting the NF-ᴋB pathway, ↑ binding of Nrf2 to RE, ↑ protein level of nuclear Nrf2, Keap1 released from its complex with Nrf2 and interacts with IKKβ to inhibit NF-ᴋB Grape seed

oxLDL-treated

procyanidins

RAW264.7

45 µg/ml

ABCA1 mRNA ↑

(Terra et al., 2009)

macrophages Piperine

ABCA1 mRNA ↔,

(Wang et

macrophages or

ABCA1 protein ↑,

al., 2017a)

cholesterol-treated

interference with

THP-1

calpain-mediated

macrophages

degradation of ABCA1,

THP-1

50 µM

calpain activity ↓ Evodiamine

THP-1

1 – 10 µM

direct binding to

(Wang, L. et

macrophages and

ABCA1 leading to

al., 2018)

cell-free assays

increased ABCA1

(surface plasmon

stability and increased

resonance)

ABCA1 protein level, ABCA1 mRNA ↔

-/-

apoE mice

10 mg/kg/day for size of atherosclerotic

(Wei et al.,

4 weeks

2013)

lesions, hyperlipidemia and hepatic

macrovesicular steatosis ↓, possibly through TRPV1 Rutaecarpine

RAW264.7

0.035 – 34.8 µM

macrophages,

ABCA1 mRNA and

(Xu et al.,

protein ↑

2014)

HepG2 cells Primary murine

not given, data

macrophages from

not shown

ABCA1 protein ↑

female ICR mice (stably transfected)

LXRα-LBD/Gal4: induction of ABCA1

HepG2 cells

EC50 = 0.0030

transcription, binding to

µM

the LXRα-LBD and

LXRβ-LBD/Gal4: LXRβ-LBD, EC50 = 0.0014 µM -/-

apoE mice on a

10 – 40

atherosclerotic lesions,

high-fat diet

mg/kg/day for 8

plasma total

weeks

cholesterol, LDL cholesterol and triglyceride levels ↓

Leonurine

ABCA1 mRNA and

(Jiang et al.,

THP-1

protein ↑, PPARγ and

2017)

macrophages

LXRα mRNA and

oxLDL-loaded

5 – 80 µM

protein ↑ apoE-/- mice

10 mg/kg/day for atherosclerotic lesion 8 weeks

size in aortic roots, serum triglycerides, total cholesterol and LDL cholesterol ↓, HDL cholesterol ↑, PPARγ, LXRα, ABCA1 and ABCG1 protein levels in aortic roots ↑

Diosgenin

acLDL-loaded

10 – 80 µM

ABCA1 protein ↑,

(Lv et al.,

THP-1

suppression of miRNA-

macrophages,

19b

2015)

acLDL-loaded MPMs apoE-/- mice on a

1% of food (w/w)

ABCA1 expression ↑ in

Western diet

for 8 weeks

the aortic arch, increase in RCT, atherosclerotic lesion areas ↓ in the aorta

Methyl

THP-1

10 – 200 µM

ABCA1 mRNA and

(Ma et al.,

protodioscin

macrophages/acL

(THP-1), 60 µM

protein ↑, SREBP1c

2015)

DL-loaded THP-1

(HepG2)

and SREBP2 mRNA

Fucosterol

macrophages,

and protein ↓, levels of

HepG2 cells

miRNA-33a/b ↓

HEK293 cells

cell-free assay

100 and 200 µM

1 nM – 100 µM

(time resolved

activation of LXRα and

(Hoang et

LXRβ via the LBDs

al., 2012b)

ligand of LXRα and LXRβ

fluorescence energy transfer) THP-1

100 and 200 µM

LXRβ mRNA ↑

macrophages

Vitamin D

ABCA1, LXRα and

Caco-2 cells

100 and 200 µM

ABCA1 mRNA ↑

HepG2 cells

100 and 200 µM

ABCA1 mRNA ↑

Yucatan

vitamin D-

ABCA1 mRNA and/or

(Yin et al.,

microswine on a

sufficient diet

protein ↑ in liver and

2015)

high-cholesterol

(1000 IU/d) or

common carotid

diet

vitamin D-

arteries, 27-

supplemented

hydroxycholesterol ↑

diet (3000 IU/d)

(liver), LXRα and LXRβ

for 48 weeks

mRNA and/or protein ↑

oxLDL-loaded

1,25(OH)2

ABCA1 mRNA and

THP-1

vitamin D3 at 10

protein ↑, LXRα protein

macrophages

nM

↑, CYP27A1 mRNA

and protein ↑ via a VDR-dependent JNK1/2 signaling pathway (oxLDL-loaded)

1,25(OH)2

ABCA1 protein ↑,

HepG2 cells

vitamin D3 at 10

CYP27A1 protein ↑,

nM

levels of 27hydroxycholesterol ↑

VDR knockout

no significant

(Wang et

mice

difference in ABCA1

al., 2009)

mRNA levels compared to WT mice Citrulline

THP-1

0.01 – 1 mM

macrophages

ABCA1 mRNA and

(Uto-Kondo

protein ↑, mRNA

et al., 2014)

stability of ABCA1 ↑ HMDMs in the

1.6 g citrulline

ABCA1 mRNA and

presence of

twice daily for 1

protein ↑

autologous sera

week

obtained from healthy volunteers with citrulline consumption S-allyl cysteine

THP-1

10 – 40 mM

macrophages

ABCA1 mRNA and

(Malekpour-

protein ↑

Dehkordi et al., 2013)

Taurine

THP-1

10 – 100 µM

macrophages

ABCA1 mRNA and

(Hoang et

protein ↑, LXRα mRNA

al., 2012a)

and protein ↑ 10 – 100 µM

ABCA1 mRNA ↑

CHO-K1 cells

10 – 100 µM

activation of LXRα

cell-free assays

10 nM – 1 mM

direct ligand of LXRα

(time resolved

and 100 µM

HepG2 cells, Caco-2 cells

fluorescence

energy transfer and limited protease digestion analysis) Allicin

oxLDL-loaded

ABCA1 mRNA and

(Lin et al.,

THP-1

protein ↑, PPARγ and

2017)

macrophages

LXRα protein ↑

Astragalus

TNF-α treated

polysaccharides

5 mg/ml

25 – 100 µg/ml

rescue of the

(Wang et

oxLDL-loaded

downregulation of

al., 2010)

THP-1

ABCA1 mRNA and

macrophages

protein induced by TNF-α, attenuation of the nuclear translocation of NF-ᴋB p65 induced by TNF-α

Falcarindiol

THP-1

10 µM

macrophages

ABCA1 mRNA and

(Wang et

protein ↑, involvement

al., 2017b)

of PPARγ, inhibition of ABCA1 degradation by inhibition of lysosomal cathepsins 6-Gingerol

HepG2 cells

50 – 200 µM

ABCA1 mRNA and

(Li, X. et al.,

protein ↑, LXRα mRNA

2018)

and protein ↑ 6-

cholesterol-loaded

Dihydroparadol

5 – 30 µM

ABCA1 mRNA and

(Wang, D.

THP-1

protein ↑, half-life of

et al., 2018)

macrophages

ABCA1 ↑, proteasomal degradation of ABCA1 ↓

Paeonol

RAW264.7 macrophages

5 – 50 µM

ABCA1 mRNA ↔,

(Li et al.,

ABCA1 protein ↑,

2015)

stability of ABCA1 ↑ by inhibiting calpain activity due to

increased interaction with its endogenous inhibitor calpastatin, HO-1 is required for inhibition of calpain activity and ABCA1 ↑ apoE-/- mice on a

150 mg/kg/day

ABCA1 protein in

high-fat diet

for 8 weeks

aortas ↑, atherosclerotic lesion formation ↓

J774A.1

25 – 100 µg/ml

ABCA1 mRNA and

(Zhao, J.F.

protein ↑, nuclear

et al., 2013)

levels of LXRα and RXRα protein ↑, activity of LXRα and ABCA1 promoter ↑ -/-

apoE mice

100 mg/kg/day

ABCA1 and LXRα

for 4 weeks

protein in the aorta ↑, atherosclerotic lesion size ↓, serum levels of total cholesterol and triglycerides ↓