Foam cells in atherosclerosis

CCA-13117; No of Pages 8 Clinica Chimica Acta xxx (2013) xxx–xxx

Contents lists available at SciVerse ScienceDirect

Clinica Chimica Acta journal homepage: www.elsevier.com/locate/clinchim

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Invited critical review

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Foam cells in atherosclerosis☆ a

Life Science Research Center, University of South China, Hengyang, Hunan 421001, China Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, University of South China, Hengyang, Hunan 421001, China c Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, AL 35294-0012, USA d Department of Pediatrics and Group on the Molecular and Cell Biology of Lipids, University of Alberta, Edmonton, Alberta T6G 2S2, Canada b

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Article history: Received 25 April 2013 Received in revised form 4 June 2013 Accepted 6 June 2013 Available online xxxx

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Atherosclerosis is a chronic disease characterized by the deposition of excessive cholesterol in the arterial intima. Macrophage foam cells play a critical role in the occurrence and development of atherosclerosis. The generation of these cells is associated with imbalance of cholesterol influx, esterification and efflux. CD36 and scavenger receptor class A (SR-A) are mainly responsible for uptake of lipoprotein-derived cholesterol by macrophages. Acyl coenzyme A:cholesterol acyltransferase-1 (ACAT1) and neutral cholesteryl ester hydrolase (nCEH) regulate cholesterol esterification. ATP-binding cassette transporters A1(ABCA1), ABCG1 and scavenger receptor BI (SR-BI) play crucial roles in macrophage cholesterol export. When inflow and esterification of cholesterol increase and/or its outflow decrease, the macrophages are ultimately transformed into lipid-laden foam cells, the prototypical cells in the atherosclerotic plaque. The aim of this review is to describe what is known about the mechanisms of cholesterol uptake, esterification and release in macrophages. An increased understanding of the process of macrophage foam cell formation will help to develop novel therapeutic interventions for atherosclerosis. © 2013 The Authors. Published by Elsevier B.V. All rights reserved.

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Keywords: Macrophages Foam cells CD36 SR-A ACAT1 nCEH ABCA1 ABCG1 SR-BI

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Introduction . . . . . . . . . Cholesterol uptake . . . . . . 2.1. CD36 . . . . . . . . . 2.2. SR-A . . . . . . . . . . 3. Cholesterol esterification . . . . 3.1. ACAT1 . . . . . . . . . 3.2. nCEH . . . . . . . . . 4. Cholesterol efflux . . . . . . . 4.1. ABCA1 . . . . . . . . . 4.2. ABCG1 . . . . . . . . . 4.3. SR-BI . . . . . . . . . 5. Conclusion and future directions Acknowledgment . . . . . . . . . . References . . . . . . . . . . . . .

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Xiao-hua Yu a, Yu-chang Fu c, Da-Wei Zhang d, Kai Yin b,⁎, Chao-ke Tang a,b,⁎⁎

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Abbreviations: ABCA1, ATP-binding cassette transporter A1; ABCG1, ATP-binding cassette transporter G1; SR-BI, scavenger receptor BI; SR-A, scavenger receptor class A; ACAT1, acyl coenzyme A:cholesterol acyltransferase-1; nCEH, neutral cholesteryl ester hydrolase; ox-LDL, oxidized low-density lipoprotein; HDL, high-density lipoprotein; apoA-I, apolipoprotein A-I; LDLR, low-density lipoprotein receptor; apoE, apolipoprotein E; CE, cholesterol ester; FC, free cholesterol; LXR, liver X receptor; RXR, retinoid X receptor; PPAR-γ, peroxisome proliferator-activated receptor-γ; ERK1/2, extracellular signal-regulated kinases 1 and 2; PPREs, PPAR response elements; PKB, protein kinase B; PKC, protein kinase C; TGF-β, transforming growth factor-β; MAPK, mitogen-activated protein kinase; RCT, reverse cholesterol transport; PI3K, phosphatidylinositol 3-kinase; AGE, advanced glycation end products. ☆ This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-No Derivative Works License, which permits non-commercial use, distribution, and reproduction in any medium, provided the original author and source are credited. ⁎ Corresponding author. Tel./fax: +86 734 8281852. ⁎⁎ Correspondence to: Institute of Cardiovascular Research, University of South China, Hengyang, Hunan 421001, China. Tel./fax: +86 734 8281853. E-mail addresses: [email protected] (K. Yin), [email protected] (C. Tang). 0009-8981/$ – see front matter © 2013 The Authors. Published by Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.cca.2013.06.006

Please cite this article as: Yu X, et al, Foam cells in atherosclerosis, Clin Chim Acta (2013), http://dx.doi.org/10.1016/j.cca.2013.06.006

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Cholesterol uptake is a pathway by which extracellular modified LDL are ingested by macrophages via receptors-mediated phagocytosis and pinocytosis. SRs such as SR-A and CD36 have been implicated in this process. In vitro studies have shown that CD36 and SR-A account for 75% to 90% of ox-LDL internalization by macrophages, whereas other SRs cannot compensate for their absence [4]. Thus, CD36 and SR-A are the most important receptors responsible for the uptake of modified lipoproteins by macrophages.

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2.1. CD36

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CD36 is first identified as the platelet glycoprotein III b/IV, an 88 kDa heavily glycosylated transmembrane protein that belongs to SR class B family. It consists of an extracellular domain flanked by two transmembrane and two cytoplasmic domains. CD36 functions

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Atherosclerotic diseases are the major causes of mortality and morbidity in the world. Formation of macrophage foam cells in the intima is a major hallmark of early stage atherosclerotic lesions. Uncontrolled uptake of oxidized low-density lipoprotein (ox-LDL), excessive cholesterol esterification and/or impaired cholesterol release result in accumulation of cholesterol ester (CE) stored as cytoplasmic lipid droplets and subsequently trigger the formation of foam cells. Scavenger receptors (SRs), CD36 and SR class A (SR-A) are the principal receptors responsible for the binding and uptake of ox-LDL in macrophages [1]. Acyl coenzyme A:cholesterol acyltransferase-1 (ACAT1) and neutral cholesteryl ester hydrolase (nCEH) play a critical role in cholesterol esterification [2]. ATP-binding cassette (ABC) transporter A1(ABCA1), ABCG1 and scavenger receptor-BI (SR-BI) mediate cholesterol export from macrophages [3]. This review focuses on the recent developments in our knowledge of the roles and regulation of these receptors, enzymes and transporters in the formation of macrophage foam cells.

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as a high-affinity receptor for ox-LDL. A domain located between amino acids 155 and 183 of CD36 involves in ox-LDL binding. Other ox-LDL binding sites have also been reported such as amino acids 28–93 and possibly 120–155. Binding of ox-LDL to CD36 leads to endocytosis through a lipid raft pathway that is distinct from the clathrin-mediated or caveolin internalization pathways. The pathogenic role of ox-LDL in atherosclerosis largely depends on CD36. A recent study revealed that plasma soluble CD36 correlates significantly with markers of atherosclerosis, insulin resistance and fatty liver in a nondiabetic healthy population [5]. Patients with acute coronary syndromes exhibit a significant increase in CD36 expression in circulating monocytes, which can be inhibited by a 6-month treatment of atorvastatin [6]. Small molecules with anti-CD36 activity have been shown to decrease postprandial hyperlipidemia and protect against atherosclerosis [7]. In addition, the 573A allele of CD36 has a protective effect against atherosclerosis development while the 591T allele is a cardiovascular risk factor [8]. On the other hand, Moore and colleagues reported that apoE−/− mice lacking CD36 or SR-A display increased aortic sinus atherosclerotic lesion area and abundant macrophage foam cells in the aortic intima despite reductions in peritoneal macrophage CE accumulation in vivo [9]. Moreover, clinical studies show that patients with CD36 deficiency are associated with severe and enhanced atherosclerotic diseases [10]. Therefore, the role of CD36 as a proatherogenic mediator of ox-LDL uptake in vivo needs to be reassessed. CD36 is highly expressed in macrophages and its expression is regulated by multiple factors (Fig. 1). Recently, Inoue et al. reported that astaxanthin (ASX), an oxygenated carotenoid (xanthophyll), significantly increases CD36 levels in peritoneal macrophages by stimulating peroxisome proliferator-activated receptor-γ (PPARγ) [11]. On the other hand, curcumin, a potent antioxidant extracted from Curcuma longa, induces a PPARγ-independent CD36 overexpression through upregulating nuclear erythroid-related factor 2(Nrf2) [12]. Additionally, Gao et al. reported that palmitate increases CD36 expression in monocytes through the regulation of de novo ceramide synthesis [13]. Supplementation of the mushroom Agaricus blazei for 12 weeks markedly elevates CD36 expression and plaque vulnerability in apoE−/− mice,

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Fig. 1. Regulation of CD36 and SR-A expression in macrophages. CD36 expression is induced by ASX and inhibited by TSIIA and quercitrin via PPARγ pathway. Palmitate increases CD36 levels while kaempferol, EM-1, squalene and walnut reduce its levels. Curcumin also upregulates CD36 expression through promoting Nrf-2 nuclear translocation but decreases SR-A protein expression via UPS. Berberine, Kv1.3 and TNF-α enhance SR-A levels, whereas MLPE and H2S diminish its levels. RXR: retinoid X receptor.

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2.2. SR-A

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SR-A, a 77-kDa cell surface glycoprotein, is a member of class A SR family. The human and murine SR-A genes are located on chromosome 8 and can be transcribed to produce three (SR-AI/II/III) and two SR-A splice variants, respectively. SR-A is highly expressed in macrophages and mediates the uptake of ox-LDL into macrophages. Inhibition of SR-A in macrophages significantly ameliorates foam cell formation and atherosclerosis in apoE−/− mice [22]. Silencing of SR-A or CD36 alone reduces atherogenesis in LDL receptor (LDLR)-deficient apolipoprotein B100 mice, whereas simultaneous silencing of both receptors has no beneficial effect, suggesting that the compensatory upregulation of the two receptors is sufficient for the uptake of modified LDL [23]. Conversely, completely knockout of SR-A alone aggravates atherosclerosis despite of reduced peritoneal macrophage lipid accumulation [9], but combined deletion of SR-A and CD36 reduces atherosclerotic lesion complexity without affecting foam cell formation in hyperlipidemic mice, indicating that specific inhibition of these pathways in vivo may promote plaque stability [24]. Thus, further studies are necessary to clarify the role of SR-A in atherosclerosis. The expression level of SR-A is upregulated by a variety of agents (Fig. 1). Treatment of ox-LDL stimulates SR-A expression and promotes the uptake of ox-LDL into macrophages. Li and colleagues reported that berberine significantly elevates mRNA and protein levels of SR-A in mouse RAW264.7 cells through inhibiting PTEN expression and sustaining Akt activation [25]. Proinflammatory cytokines such as TNF-α also induce SR-A expression but via suppression of nuclear factor-κB (NF-κB) signaling [26]. More recently, voltage-gated potassium channel Kv1.3 has been shown to upregulate SR-A expression in human monocyte-derived macrophages, revealing that specific Kv1.3 blockade may represent a novel strategy to modulate cholesterol metabolism in macrophages [27]. Taken together, these findings indicate that inhibition of these agents may reduce the uptake of ox-LDL by macrophages and then prevent the formation of foam cells. Hydrogen sulfide (H2S), curcumin and mulberry leaf polyphenolic extracts (MLPE) have been reported to decrease SR-A expression (Fig. 1). Our previous studies have shown that H2S reduces SR-A expression and foam cell formation in human monocyte-derived macrophages via the K(ATP)/ERK1/2 pathway [28]. Curcumin decreases SR-A protein levels in macrophages through the ubiquitin/proteasome system(UPS)-dependent proteolysis [29]. On the other hand, MLPE inhibits PPARγ and then reduces macrophage SR-A levels, suggesting a protective role of MLPE in regulating intracellular lipid homeostasis within the intima [30].

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In addition to cholesterol uptake, the balance of free cholesterol (FC) and CE is also critical for the regulation of intracellular cholesterol content in macrophage foam cells. After internalization, lipoproteins are delivered to the late endosome/lysosome, where CE is hydrolyzed into FC by lysosomal acid lipase (LAL). To prevent the FC-associated cell toxicity, the FC released is re-esterified on the endoplasmic reticulum (ER) by ACAT1 and stored in cytoplasmic lipid droplets. If this persistently occurs, excessive CE will accumulate in macrophages, thereby resulting in the formation of foam cells. These cells are often referred to as foam cells because of their characteristic “foamy” appearance. The resulting CE are hydrolyzed by nCEH to release FC for transporters-mediated efflux, which is increasingly being recognized as the rate-limiting step in FC outflow [31]. Thus, the cycle of esterification and hydrolysis of CE is one of the key steps in maintaining intracellular cholesterol homeostasis, and ACAT1 and nCEH play a crucial role in the process.

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indicating a proatherogenic property of mushroom A. blazei [14]. In contrast, a dietary compound quercitrin inhibits CD36 expression in murine macrophages through interfering with PKC/PPARγ signaling cascades [15]. Tanshinone IIA (TSIIA), a lipophilic diterpene isolated from Salvia miltiorrhiza Bunge (Danshen), also decreases CD36 levels in ox-LDL treated macrophages by antagonism of PPARγ [16]. Similarly, endomorphin-1(EM-1), a member of the endogenous opioid peptides family, and squalene, one of the components of olive oil, downregulate CD36 expression and prevent lipid accumulation in human lipid-laden macrophages [17,18]. Treatment of macrophages with kaempferol inhibits c-Jun/activator protein-1 (AP-1) nuclear translocation and leads to the downregulation of CD36 expression [19]. Atheroprotective effect of dietary intake of walnut that enriches in n-3 polyunsaturated fatty acids and antioxidant compounds, is associated with reduced CD36 expression in apoE−/− mice [20]. In addition, the combined treatment of interferon γ and tumor necrosis factor α (TNF-α) significantly reduces CD36 levels [21]. Thus, these factors may act as novel modulators for macrophage-to-foam cell transformation.

3.1. ACAT1

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3.2. nCEH

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ACAT1 is an integral membrane protein that converts FC into the storage form of CE. It has already been reported that ACAT1 deficiency increases the synthesis and efflux of FC in mouse peritoneal macrophages while its overexpression promotes CE accumulation and macrophage-derived foam cell formation [32,33]. However, the role of ACAT1 in atherosclerosis is currently under debate. Kusunoki et al. revealed that ACAT1 inhibition attenuates atherosclerosis in apoE −/− mice [34]. On the other hand, mice lacking macrophage-derived ACAT1 show accelerated atherosclerosis [35,36]. This may be due to the cytotoxic effects of increased FC levels, which crystallize in macrophage foam cells. The formation of cholesterol crystals not only destroys cholesterol metabolism during the development of atherosclerosis, but also facilitates the secretion of inflammatory mediators such as IL-1β and IL-18 [37]. Taken together, the effects of ACAT1 on atherosclerosis remain to be further investigated. Numerous steps have been implicated in the modulation of ACAT1 expression (Fig. 2). Insulin has been shown to enhance ACAT1 expression in THP-1 macrophages via MAP kinases (MAPK)/CCAAT/enhancer binding protein α(C/EBPα) signaling pathway [38]. Yang et al. observed that voltage-gated potassium channel Kv1.3 significantly upregulates ACAT1 expression and increases percentage of CE in human monocyte-derived macrophages exposed to ox-LDL [27]. Chlamydia pneumoniae (C. pneumoniae) infection is reported to increase ACAT1 expression and disturb cholesterol homeostasis through c-Jun NH(2) terminal kinase (JNK)/PPARγ dependent signal transduction pathways [39]. Leptin, an adipose tissue-derived hormone, accelerates CE accumulation in human monocyte-derived macrophages by increasing ACAT1 expression via Janus-activated kinase 2 (JAK2) and PI3K [40]. In contrast, treatment of cultured THP-1 macrophages in vitro with an angiotensin receptor blocker, candesartan, leads to a decrease in ACAT1 expression [41]. Incretins such as glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are also able to decrease the levels of ACAT1 by cAMP activation [42]. Our recent studies showed that H2S inhibits macrophage foam cell formation by suppressing ACAT1 expression via K(ATP)/ERK1/2 pathway [28]. Additionally, ghrelin, an endogenous ligand of the growth hormone secretagogue receptor (GHS-R), lowers the expression of ACAT1 in THP-1 macrophages via pathways involving GHS-R and PPARγ, indicating a protective role for ghrelin in controlling cellular lipid accumulation [43].

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The esterification of FC into CE by ACAT1 is opposed by nCEH, 252 which hydrolyzes CE to cholesterol for efflux out of the cells. nCEH 253

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The first step of RCT is cholesterol efflux, namely, accumulated cholesterol is removed from macrophages in the subintima of the vessel wall through transporters or other mechanisms such as passive diffusion, and then collected by high-density lipoprotein (HDL) or

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apolipoprotein A-I (apoA-I). Active transport via transporters including the best characterized ABCA1, ABCG1 and SR-BI is mainly responsible for the bulk efflux of cholesterol from macrophages onto extracellular acceptors.

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is a single-membrane-spanning type II membrane protein including three domains: N-terminal, catalytic, and lipid-binding domains. The N-terminal domain acts as a type II signal anchor sequence to recruit nCEH to the ER with its catalytic domain within the lumen [44]. N-linked glycosylation at Asn270 is important for its enzymatic activity. One recent study by Igarashi et al. showed that overexpression of human nCEH promotes the hydrolysis of CE and thereby stimulates cholesterol mobilization from THP-1 macrophages while knockdown of nCEH markedly accelerates the formation of foam cells, further conforming the key role for nCEH in maintaining intracellular cholesterol equilibrium [45]. Moreover, genetic ablation of nCEH also facilitates the development of atherosclerosis in apoE−/− mice without affecting their serum lipid profile [46]. Conversely, macrophage-specific overexpression of nCEH leads to a significant reduction in atherosclerotic lesion area in LDLR−/− mice because of enhanced FC efflux and reverse cholesterol transport (RCT) [47]. Overall, these results demonstrate the antiatherogenic role of nCEH and indicate that this enzyme is a promising target for the treatment of atherosclerosis. nCEH is robustly expressed in macrophages as well as in atherosclerotic lesions. Polyunsaturated fatty acid (PUFA), insulin and IL-33 have been described to modulate its expression (Fig. 2). Napolitano and colleagues have reported that PUFA derived from corn oil can induce nCEH expression in J774 macrophages [48]. On the other hand, insulin significantly suppresses the expression of nCEH in THP-1 macrophages, partially accounting for the potential molecular mechanism of atherogenesis in type 2 diabetes with hyperinsulinemia [49]. IL-33, a recently discovered member of the IL-1 cytokine family, also reduces nCEH mRNA levels in primary human monocyte-derived macrophages by activating ST-2/NF-κB signaling pathway [50,51]. Variety of other factors that can regulate nCEH expression will be probably found in later researches.

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Fig. 2. Regulation of ACAT1 and nCEH expression in macrophages. ACAT1 is upregulated by insulin, Kv1.3, C. pneumoniae and leptin but downregulated by candesartan, GLP-1, GIP, H2S and ghrelin. PUFA increases nCEH expression while insulin and IL-33 decrease its expression.

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ABCA1 is a member of the large superfamily of ABC transporters. It is now well established that ABCA1 plays a critical role in the prevention of macrophage foam cell formation and atherosclerosis by mediating the active transport of intracellular cholesterol and phospholipids to apoA-I, the major lipoprotein in HDL. Bochem and colleagues have demonstrated that ABCA1 mutation carriers show lower HDL-cholesterol (HDL-C) levels and a larger atherosclerotic burden compared with controls [52]. Unexpectedly, mice lacking ABCA1 and SR-BI display severe hypocholesterolemia and foam cell accumulation, but have no atherosclerosis, which is mainly due to the absence of proatherogenic lipoproteins [53]. ABCA1 overexpression in the liver of LDLR−/− mice results in accumulation of proatherogenic lipoproteins and enhanced atherosclerosis [54]. Thus, in regard to these contradictory observations, a careful re-evaluation of ABCA1 as a potent antiatherogenic agent is necessary. The expression of ABCA1 is highly regulated by multiple processes (Fig. 3). Lee et al. observed that quercetin stimulates PPARγ/liver X receptor α (LXRα) signaling and then increases ABCA1 expression and cholesterol efflux from THP-1 macrophages, indicating that ingestion of quercetin or quercetin-rich foods may be an effective way to lower the risks of atherosclerosis [55]. Studies from our laboratory showed that apelin-13, a recently discovered adipocytokine, enhances ABCA1 expression in THP-1 macrophage-derived foam cells via activating the PKCα pathway and inhibiting calpain activity [56]. Toll-like receptor 2 (TLR2) agonist Pam(3)CSK(4) raises ABCA1 levels in RAW 264.7 macrophages via activation of PKC-η/phospholipase D2 (PLD2) signaling pathway [57]. S-allylcysteine, the most abundant organosulfur compound in aged garlic extract, also elevates ABCA1 content in human THP-1 macrophages [58]. On the other hand, unsaturated fatty acids suppress ABCA1 expression in RAW 264.7 macrophages by two distinct mechanisms: LXR-dependent transcriptional repression possibly through modulating histone acetylation states, and LXR-independent posttranslational inhibition [59]. Our previous

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studies indicate that IL-18 and IL-12 synergistically decrease ABCA1 levels in THP-1 macrophage-derived foam cells through the IL-18 receptor (IL-18R)/NF-κB/zinc finger protein 202 (ZNF202) signaling pathway [60]. In addition, miR-26 prevents ABCA1 expression and subsequent cholesterol efflux from macrophages to apoA-I via targeting LXRα, indicating a novel regulatory role of miR-26 in cellular lipid accumulation within the intima [61]. Thus, miR-26 inhibitors can be potentially used to treat atherosclerosis.

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4.2. ABCG1

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ABCG1 mediates cholesterol removal from macrophages to HDL particles but not to lipid-free apoA-I. It has been shown that a functional genetic variant in the ABCG1 promoter is associated with an increased risk of myocardial infarction and ischemic heart disease in the general population [62]. Lack of macrophage ABCG1 has been reported to cause a modest increase in atherosclerotic lesions [63]. However, two other independent groups reported that LDLR−/− mice lacking macrophage ABCG1 show decreased atherosclerotic lesions [64,65]. Most recently, Meurs and colleagues found that the absence of ABCG1 leads to increased lesions in early stage of atherosclerosis but causes retarded lesion progression in more advanced stage of atherosclerosis in LDLR−/− mice, suggesting that the influence of ABCG1 deficiency on lesion development depends on the stage of atherogenesis [66]. Therefore, the impact of ABCG1 on the development of atherosclerosis is complex and needs to be further investigated. The regulation of ABCG1 expression has similarities with that of ABCA1, consistent with a shared role in cholesterol export (Fig. 3). Cineole, a small aroma compound in teas and herbs, induces ABCG1 expression in macrophages through the activation of LXR [67]. Fucosterol, a sterol that is abundant in marine algae, is also able to increase ABCG1 levels in a LXR-dependent mechanism [68]. Consumption of extravirgin olive oil (EVOO) for 12 weeks induces a concentrationdependent upregulation of ABCG1 expression in human macrophages

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Fig. 3. Regulation of ABCA1, ABCG1 and SR-BI expression in macrophages. ABCA1 expression is induced by apelin-13, Pam(3)CSK(4) and quercetin but inhibited by miR-26 and IL-18 plus IL-12. Cineole, EVOO and fucosterol upregulate ABCG1 expression by activating LXR, whereas LPS downregulates its expression. In addition, PCA increases ABCG1 levels via suppression of miR-10b. Res, LA, hydrogen and coffee lead to a significant elevation in the SR-BI levels while PAPP-A treatment reduces its levels. P: phosphorylation, APJ: G-protein coupled receptor.

[69]. Protocatechuic acid (PCA), a gut microbiota metabolite of cyanidin-3 to 0-β-glucoside, exerts an antiatherogenic effect partially through inhibition of miR-10b-mediated downregulation of ABCG1 expression, indicating that gut microbiota is a potential novel target for prevention and treatment of atherosclerosis [70]. Conversely, subclinical low-dose lipopolysaccharide (LPS) potently reduces the expression of ABCG1 in bone marrow-derived macrophages through interleukin-1 receptor-associated kinase 1(IRAK-1)/glycogen synthase kinase 3β (GSK3β)/retinoic acid receptor α (RARα) signaling pathway, revealing a novel intracellular network regulated by low-dose endotoxemia [71].

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SR-BI promotes cholesterol efflux from macrophages to HDL. A genetic variant of the SR-BI in humans leads to a reduction in cholesterol efflux from macrophages but has no significant increase in atherosclerosis [72]. On the other hand, inactivation of macrophage SR-BI facilitates atherosclerotic lesion development in apoE−/− mice [73]. However, a recent report suggests that the presence of macrophage SR-BI inhibits advanced atherosclerotic lesion but promotes early lesion development in LDLR−/− mice, indicating a unique dual role for macrophage SR-BI in the pathogenesis of atherosclerosis [74]. SR-BI is also highly expressed in the liver. Hepatic SR-BI expression is a positive regulator of the rate of RCT from macrophages to the liver, bile, and feces. Of note, inhibition of hepatic SR-BI using RNA interference technique reduces atherosclerosis in rabbits fed with cholesterol-rich diet, indicating that the effect of SR-BI on atherogenesis in rabbits is different from the one seen in rodents [75]. Therefore, more studies are needed to elucidate the role of SR-BI in regulating atherosclerosis. Multiple factors regulate SR-BI expression (Fig. 3). Resveratrol (Res), a bioactive molecule used in dietary supplements, and 13-hydroxy linoleic acid (LA), a natural PPAR agonist, induce SR-BI expression in macrophages through PPARγ/LXRα pathway [76,77]. Uto-Kondo et al. recently reported that coffee intake significantly

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5. Conclusion and future directions

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The balanced of cholesterol influx, esterification and release is necessary to avoid lipid overload within macrophages, and ultimately, atheroma development. Under atherogenic conditions, efflux of cholesterol is decreased due to reduced expression of ABCA1, ABCG1 and SR-BI; however its uptake is increased due to enhanced expression of CD36 and SR-A as well as excess esterification of cholesterol occurs because of higher ACAT1 level and lower nCEH level. This leads to excessive CE accumulation as lipid droplets in macrophages, thereby contributing to the formation of foam cells (Fig. 4). Therefore, targeting these three pathways could be a viable approach to regulate cholesterol metabolism in macrophages and treat atherosclerotic cardiovascular diseases. K-604 and rimonabant, recently identified as potent inhibitors of ACAT1, have been shown to inhibit macrophage foam cell formation and retard atherosclerosis in apoE−/− mice [81,82]. A growing body of evidence indicates that food components play an important role in prevention of foam cell formation by reducing cholesterol uptake and/or promoting its removal. For instance, seven phenolic acids, the major bioactive compounds in blueberries,

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have been recently reported to attenuate the formation of macrophage foam cells through downregulation of CD36 expression and upregulation of ABCA1 expression [83]. Notably, despite strong inverse association of plasma HDL levels with the risks of atherosclerotic cardiovascular diseases, HDL-raising therapies are not always effective. A randomized and placebo-controlled intervention trial has demonstrated that niacin increases HDL-C but does not reduce cardiovascular events [84]. Moreover, a large human genetics study shows that genetic variants that enhance HDL-C levels do not necessarily associate with myocardial infarction risk [85]. As a result, additional studies are needed to evaluate the role of new compounds to raise HDL-C levels or modify HDL composition and functionality. In addition to these receptors, enzymes and transporters, we should pay attention to the role of other molecules in cholesterol trafficking. In summary, further work is required to elucidate the diverse processes that regulate the expression and activity of these proteins, and to determine their contribution to disease protection in humans. These studies will provide more insight into their physiological roles and will reveal novel therapeutic strategies for treating atherosclerotic cardiovascular disease.

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increases SR-BI expression and HDL-mediated cholesterol efflux from macrophages via its plasma phenolic acids [78]. Hydrogen administration also raises macrophage SR-BI levels in apoE−/− mice [79]. On the other hand, pregnancy-associated plasma protein-A (PAPP-A), a newly recognized metalloproteinase in the insulin-like growth factor (IGF) system, significantly decreases SR-BI expression and promotes the formation of macrophage foam cells via IGF-1/PI3K/Akt/LXRα signaling pathway, indicating a novel mechanism for its proatherogenic effect [80].

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Fig. 4. Schematic representation of the mechanism involved in macrophage foam cell formation. Under atherogenic conditions, the increased uptake and esterification of cholesterol and/or reduced cholesterol efflux lead to excessive CE accumulation in the form of lipid droplets in the cytoplasm, thereby promoting the formation of macrophage foam cells. (+): activation, (–): inhibition.

Please cite this article as: Yu X, et al, Foam cells in atherosclerosis, Clin Chim Acta (2013), http://dx.doi.org/10.1016/j.cca.2013.06.006

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