The role of adiponectin and adipolin as anti-inflammatory adipokines in the formation of macrophage foam cells and their association with cardiovascular diseases

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Clinical Biochemistry journal homepage: www.elsevier.com/locate/clinbiochem

Review

The role of adiponectin and adipolin as anti-inflammatory adipokines in the formation of macrophage foam cells and their association with cardiovascular diseases ⁎

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Javad Sargolzaeia, Elham Chamanib, , Tooba Kazemib, Soudabeh Fallahc, , Hosna Sooria a

Department of Biochemistry, Institute Biochemistry and Biophysics, University of Tehran, Tehran, Iran Cardiovascular Diseases Research Center, Birjand University of Medical Sciences, Birjand, Iran c Department of Biochemistry, School of Medicine, Iran University of Medical Sciences, Tehran, Iran b

A R T I C L E I N F O

A B S T R A C T

Keywords: Adipoline Adiponectine Cardiovascular disease

Obesity is one of the major public health concerns that is closely associated with obesity-related disorders such as type 2 diabetes mellitus (T2DM), hypertension, and atherosclerosis. Atherosclerosis is a chronic disease characterized by excess cholesterol deposition in the arterial intima and the formation of foam cells. Adipocytokines or adipokines are secreted by the adipose tissue as endocrine glands; adiponectin and adipolin are among these adipokines that are associated with obese and insulin-resistant phenotypes. Adipolin and adiponectin are cytokines that exert substantial impact on obesity, progression of atherosclerosis, insulin resistance, and glucose metabolism. In this paper, we review the formation of macrophage foam cells, which are associated with atherosclerosis, and the macrophage mechanism, which includes uptake, esterification, and release. We also summarize current information on adipose tissue-derived hormone and energy homeostasis in obesity. Finally, the role of adipokines, e.g., adipoline and adiponectin, in regulating metabolic, cardiovascular diseases is discussed.

1. Introduction High-fat and high-cholesterol diets, especially used by people with a genetic susceptibility, leads to atherosclerosis and hypercholesterolemia. Atherosclerosis is a major cause of myocardial infarction (commonly known as heart attack) or stroke. On the other hand, cardiovascular disease has the highest mortality rate in the world, accounting for 16.7 million annual deaths worldwide [1–4]. Atherosclerosis (as a chronic disease of the arteries), shows that macrophages are generated by direct stimulation of the inflammatory signaling pathways [5,6]. It contributes significantly to atherogenesis through the uptake of the most atherogenic of all the lipoproteins and modified lowdensity lipoprotein (LDL) and via the secretion of cytokines and particle-forming enzymes [5,6]. Laminar flow and especially the arterial bifurcation sites are mostly disrupted by accumulated lipids and fibrous elements in the large vessels, and thus atherosclerosis is introduced as a highly important cardiovascular disease [7]. Low density lipoprotein cholesterol (LDL-c), as opposed to high-density lipoprotein cholesterol (HDL-c), increases the accumulation of cholesterol and causes inflammatory responses in

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the arterial wall. Increased LDL-c leads some cholesterols into blood vessels whereby changes such as accumulation and oxidation [8–11]. Nonetheless, Toll-like receptors (TLRs) are identified as pattern recognition receptors in the macrophage by modified LDL-c, thereby they activate the proinflammatory signaling pathways and macrophages surround the modified LDL-c. Accordingly, the accumulation of cholesterol is promoted by TLR signaling [8–10]. The signals of microbial products and stress-activated NLRP3 inflammasome can induce the activation of caspase 1, the cleavage of proIL 1β and pro-IL 18, and the subsequent secretion of IL 1β, IL 18, and possibly of pyroptosis (inflammasome consists of the NOD-like receptor NLRP3, caspase 1, and the adaptor protein ASC) [12–14]. Activation of the NLRP3 inflammasome is promoted via increased TLR activity, cytokine production, and the subsequent formation of intracellular cholesterol crystals. Many studies have investigated atherogenesis, i.e., the formation of abnormal fats in the arterial wall. For instance, lesions of atherosclerosis and platelet derivatives in foam cells have been studied [15,16]. Foam cells include accumulation of cholesterol in macrophages, which causes primary lesions of atherosclerosis in the subendothelial layer, subsequently leading to the

Corresponding authors. E-mail addresses: [email protected] (E. Chamani), [email protected] (S. Fallah).

https://doi.org/10.1016/j.clinbiochem.2018.02.008 Received 29 November 2017; Received in revised form 12 February 2018; Accepted 13 February 2018 0009-9120/ © 2018 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.

Please cite this article as: Sargolzaei, J., Clinical Biochemistry (2018), https://doi.org/10.1016/j.clinbiochem.2018.02.008

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stored as cytoplasmic lipid droplets. When the re-esterification process increases, thus increases the internalization and accumulation of reesterified FC or CE in macrophages foam cells [26]. The reason for the term foam is that the lipid occupies a large volume of the cell and appears “foamy” [26]. The slowest step in chemical kinetics is known as the rate determining step (RDS). In the FC outflow, RDS is catalyzed by the neutral cholesteryl ester hydrolase (nCEH), which converts the CE to FC and is released via transporters-mediated efflux. Thus, nCEH and ACAT1 are very important for cholesterol esterification [27,28]. Externalization of the accumulated cholesterol from macrophages occurs via transporters or passive diffusion. Therefore, free cholesterol is collected by apolipoprotein A-I (apoA-I) or HDL-c. The most important and principle responsibility is efflux of large volumes of cholesterol from macrophages onto extracellular acceptors through active transport [29,30]. Among the most important extracellular transporters are ATP-binding cassette (ABC) transporter A1(ABCA1), ABCG1 and scavenger receptor-BI (SR-BI). Therefore, ABCG1, ABCA1 and SRB1 are necessary to remove cholesterol from macrophages [29,30]. Balance, esterification and release of cholesterol influx are significant to prevention from arteriosclerosis. Artherogenic reduces the expression of the ABCA1, ABCG1 and SR-BI as a result of the decreased amounts of cholesterol efflux. Increased expression of CD36 and SR-A, decreased nCEH levels, and increased levels of ACTA1 raise the amount of cellular esterified cholesterol [31,32]. Accordingly, the formation of lipid droplets in macrophages due to excessive accumulation of CE can be considered as an important contributor to foam cells formation [31,32]. With regard to the central role of these three distinct pathways in the regulation of cholesterol in macrophages, they can be used to treat atherosclerotic cardiovascular diseases (Fig. 1). The accumulation of cholesterol and inflammation in macrophages are reduced by counter-regulatory mechanisms. The liver X receptor (LXR) is activated by specific oxysterols created by the formation of cholesterol. LXR is characterized by two isoforms, including LXRα and LXRβ [33]. LXRs reduce substantially the low-density lipoprotein cholesterol (LDL-c) receptor uptake by the LDL receptor, and regulate the reverse cholesterol transport and cellular cholesterol, which is activated by desmosterol (as intermediate cholesterol biosynthesis) and oxysterols (derived from cholesterol) [33]. Many promoters of the genes involved in the metabolism of cholesterol and lipogenesis have retinoid X receptors (RXRs) that are coupled with the transcription factors of LXRα and LXRβ. ATP-binding cassette transporters (ABC transporters) are a family of membrane transport proteins that contain isoforms such as A1, G1, G5 and G8. ABC transporters require energy (ATP) to transport cholesterol and other lipids across the cell membrane. These transporters are upregulated by a variety of anti-inflammatory activities such as LXR-RXR heterodimers. However, ABC subfamily A member 1 (ABCA1) and ABCG1 isoforms release cholesterol and consequently reduce cholesterol accumulation and attenuate TLR signaling [33]. Cholesterol efflux occurs from HDL particles and APOA1 (as a lipidpoor form of lipid that is the main protein of HDL) by transporters such as ABCG1 and ABCA1. Cholesterol is collected under the process of reverse cholesterol transport (RCT) via the lymphatics and bloodstream in their passway to peripheral tissues to the liver, and thus it is excreted by bile and feces [34,35]. LXR activity is suppressed by TLR activation, whereby the cholesterol efflux from macrophage is reduced, and in turn, TLR signaling is amplified [36,37]. Inflammatory response is enhanced by changing the cholesterol homeostasis (through the effects of acute phase response), which is a type of feedforward mechanism [38,39]. Changes in cholesterol homeostasis are effected by the innate immune system in order to amplify the inflammatory response. Thus, the RCT pathway is down-regulated by the acute phase response. Shortterm cholesterol-facilitated immune responses are useful for wound healing and infection; nonetheless, if they are long-term, they may result in atherosclerosis [40].

internalization of various types of LDL-c and their accumulation in the artery. Fatty streak lesions are found in different stages of human life. As such, aorta, coronary arteries, and cerebral arteries are usually found in the first decade, the second decade, and the third or fourth decades of life, respectively [17,18]. In the early stages of atherogenesis, macrophages remove cholesterol deposits in the arteries, meaning that the accumulated CE-LDL in macrophages generate foam cells that lead to inflammation and coronary artery disease [6,19]. In this review paper, we focus on early stages in the formation of macrophage foam cells and adiponectin and adipolin as anti-inflammatory adipokines. Their association with cardiovascular disease is also discussed. 1.1. Foam-cell formation The internalization of different forms of modified LDL-c into macrophages leads to foam cells formation in the intima, which accumulates in the arteries [21]. It is one of the serious hallmarks of atherosclerotic lesions [20,21]. Reduction of cholesterol release, excessive cholesterol esterification, and lack of control over uptake of oxidized low-density lipoprotein (ox-LDL) lead to the formation of foam cells from accumulated cholesterol ester [22,23]. The regulation of cholesterol metabolism in macrophages for cardiovascular disease and arteriosclerosis can be divided into three pathways. Firstly, the cholesterol uptake pathway refers to the internalization of 75 to 90% of the extracellular modified LDL-c in macrophage for the formation of foam cells. Internalization of extracellular modified LDL-c in the macrophage is induced by surface receptors such as Scavenger receptors (SRs), SR class A (SR-A), and CD36 via mediated phagocytosis and pinocytosis (Fig. 1) [24,25]. Secondly, free cholesterol (FC) and cholesterol ester (CE) converge into one another causing balance and regulation of the extracellular cholesterol content of the macrophage foam cells. The next step after internalization of the lipoprotein is hydrolysis via the lysosomal acid lipase (LAL) enzyme in the late endosome or lysosome. The released FC into the ER, which is re-esterified by ACAT1, is

Fig. 1. The mechanism involved in macrophage foam cell formation [110]. Factors that cause excessive CE accumulation and increased formation of macrophage foam cells in atherogenic conditions include a) the internalization of Cholesteryl-ester (CE) rich lipoproteins by macrophage receptors such as CD36 and SR-A into cells and converting them to FC, b) re-esterification of FC to CE by acyl:cholesterol acyltransferase 1 (ACAT1) in the endoplasmic reticulum (ER); if this does not happen, FC level increases, ultimately causing apoptosis, and c) downregulation of ABCA1 and ABCG1, hence reduced cholesterol efflux.

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Fig. 2. Reverse cholesterol transport (RC T) [111,112]. The liver secretes a large amount of Apolipoprotein A-1 (APOA1) compared with the intestine, and then combines APOA1 with phospholipid to form the pre-βHDL particle. In the wall of the arteries, the cholesterol released by the ABCA1 and ABCG1 transporters enters the pre-βHDL particle to from macrophages. The released cholesterol is esterified by lecithin–cholesterol acyl transferase (LCAT) to from HDL3 and HDL2. Therefore, the amount of cholesteryl esters increases. The cholesterol enters the liver into the bloodstream. There are two types of cholesterol: free cholesterol or cholesteryl ester and the cholesterol deposited by RCT. Free cholesterol and cholesteryl ester are uptaken by HDL by scavenger receptor-B1 (SCRB1), and the cholesterol ester is recycled to the HDL surface.

other hand, free cholesterol and cholesterol esters can be directly excreted in HDL-c via scavenger receptor B1 (SRB1) from the liver, and the protein portion is also recycled into blood circulation [47,48]. Therefore, cholesterol is found in the liver deposited by RCT or it is recovered by the formation of rich triglycerides and very low-density lipoproteins (VLDL) or excretion by bile via ABCG5 and ABCG8 [49,50]. Plasma cholesteryl ester transfer protein (CETP) or lipid transfer protein in humans is a heterochange protein that facilitates the transfer of cholesterol and triglyceride esters between lipoproteins. Thus, it collects triglycerides from VLDL or LDL and exchanges them for cholesterol esters in HDLs. Lipoprotein lipase (LPL) and hepatic lipase (HL) play a major role in the metabolism and hemostasis plasma lipoprotein. LPL generally hydrolyzes triglycerides from VLDL and chylomicrons, and acts specifically on triglycerides of HDL in muscle and adipose tissue expressions and HL with hydrolytic activity. In addition, all lipases are expressed in macrophages. LDL-c delivers the cholesterol to the peripheral tissues (although most of it is cleared in the liver). A small amount of cholesterol is delivered to the arterial wall that is oxidized and/or aggregated, and eventually uptaken by macrophages. After internalization into the arterial wall, it induces LTR signaling in macrophages, leading to the formation of macrophage foam cells, Myeloperoxidase (MPO) production, and ultimately inflammation (Fig. 2) [14,51,52]. ‘Lipaemia of sepsis’ was found in the late 1950s when a cholera patient showed high levels of triglyceride in the blood. Studies have shown that lipopolysaccharide (LPS), in addition to blocking RCT, triggers the accumulation of triglycerides into VLDL in the liver and clears triglycerides from VLDL. It reduces blood lipoprotein lipase, which is explained by the phenomenon of 'lipaemia of sepsis'. Endotoxins (LPS), viruses, and other toxic compounds reduce host survival, which may help with the phenomenon of 'lipaemia of sepsis' and increases VLDL in maintaining the fat level of the peripheral tissues as well as suppressing the infection [53,54]. As excess fat tissue promotes insulin resistance, the absence of selective fat pads or the loss of

1.2. RCT and the inflammatory response The concept of “reverse cholesterol transport” (RCT) was used for the first time by Glomset in 1986 to demonstrate a multi-step process in which peripheral cholesterol in plasma is collected on the way back to the liver for repulse by the bile, which is then excreted by feces [41]. The cells send extracellular receptor-mediated cholesterol to protect themselves from non-esterified cholesterol (excessive cholesterol is toxic for the cell). It is also necessary to return this peripheral cholesterol to the metabolism of cholesterol in the body (cholesterol balance and de novo synthesis). The balance between deposition and the removal of arterial cholesterol is crucial for atherosclerosis, which results in atherosclerotic lesions due to imbalance after endothelial injury [42]. The relationship between this balance, i.e., RCT, and atherosclerosis was first suggested by Ross and Glomset. Later, Miller further developed Ross and Glomset's proposal that increased HDL-C levels enhances clearance of the artery wall and reduces cardiovascular disease (inverse relationship) [43]. The relationship between the RCT process and inflammation is described in Fig. 2. As the main protein of HDL-c, apolipoprotein A1 (APOA1) interacts with the ATP-binding cassette transporter ABC subfamily A member 1 (ABCA1) on hepatocytes, intestinal absorptive cells, and macrophages. Lipid-poor APOA1 is synthesized and secreted by the liver and/or the intestine, and subsequently acquires the phospholipid and cholesterol to form pre-βHDL particle [44]. Therefore, ABCA1 under lipid-poor conditions leads to the efflux of pre-β HDL particles and, consequently, efflux of cholesterol and phospholipid, and thus the initiation of the RCT process [45]. ABCG1 is also involved in the transfer of phospholipids and cholesterol in macrophages and increases the cholesterol efflux as HDL particles from macrophages [45,46]. HDL is a complex of multiparticulate proteins that transport all fat molecules (lipids), and another part of the fat that contains cholesterol, phospholipid, and triglyceride. Esterified cholesterol in the HDL-c is formed by the enzyme lecithin–cholesterol acyltransferase (LCAT) of free cholesterols. On the 3

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fat layers (due to the lack of a specialized section to store lipids under normal conditions) causes insulin-resistant forms [55,56]. The risk of heart disease increases by visceral obesity and insulin resistance via classical mechanisms such as dyslipidaemia, hypertension, and glucose dysmetabolism [57]. This increase leads to dysregulation in adipocyte-derived lipids, dysregulated triglyceride levels and free fatty acids, secretion of free proteins. These are responsible for regulating bioavailable functions such as antioxidant, anti-cancer, and anti-inflammatory activities referred to as adipokine or adipocytokines such as leptin, adipolin, and adiponectin [58,59]. 1.3. Adiponectin Non-esterified fatty acids (NEFAS) and triacylglycerols are passive in adipose tissue. Adipogenesis is one of the most studied phenomena in terms of its cellular differentiation, and during adipogenesis, preadipocytes differentiate into mature adipocytes. Mature adipocytes have the potential to secrete various proteins, such as cytokines, and can also be released as cytokines [57,60]. Many of the growth factors that may be involved in insulin resistance are secreted from mature adipocytes (as active endocrine and paracrine organs). CETP, angiotensinogen, adiponectin, acylation-stimulating protein (ASP), adipsin, TNF-a, IL-6 nitric oxide, adiponectin and adipolin are compounds that affect vascular and metabolic processes [57,60]. Adiponectin accounts for approximately 0.05% of the total blood plasma protein in humans and is present at concentrations ranging from 5 to 30 μg/ml [61]. Adiponectin is a glycoprotein with 244 amino acids of 30 kDa weight. Structurally, it has four parts: the signal sequence in the Nterminal region, the variable domain (between the signal sequence and the collagen-like domain), the collagen-like domain, and the globular domain that contains the C1q factor and is similar to collagen VIII and X [62]. The adiponectin trimmers consist of the connection between the triple helix and the globular domain segment. The non-covalent interactions between the collagenous sections and the hydrophobic interactions between the globular head domains are respectively the most important interactions between the triple helix regions and the globular domains [63]. The simplest forms of human adiponectin include adiponectin trimmers or low molecular weight (LMW), followed by the middle molecular weight (MMW) and high molecular weight (HMW) forms of the hexamers and multimers, respectively (Fig. 3) [64]. Adiponectin hexamers are composed of two trimmers connected in a head to head fashion via di-sulfide bonds of the collagenic region. However, adiponectin molecules do not have a distinct structure and come from a community of several trimmers such as 12-, 18-mers and possibly larger trimmers. Hexamer states (about 190 kDa) and multimers (< 300 kDa) are often found in the bloodstream [65]. Obesity is associated with decreased adiponectin (especially HMW levels). It increases the active forms of HMW and reduces LMW levels due to its low half-life (HMW is the most active isoform of adiponectin in the blood) [66]. Adiponectin production decreases in obese people. On the other hand, increased concentration of TNF-a and IL-6 (as adipocytokines, pro-inflammatory fat cells) inhibits adiponectin production in fat cells [66]. Various concentrations of adiponectin may have different effects, so that low concentrations have high anti-cancer impacts and are closely related to coronary heart disease and hypertension, while high concentrations of adiponectin have high proliferative effects, and hence, they cause tumor growth [67]. The expression of adiponectin is reduced by factors such as oxidative stress and hypoxemia, but is increased by the PPAR-y agonist (as it promotes the adipocyte differentiation) [68]. After binding to adiponectin, AdipoR1 and AdipoR2 activate and regulate a large number of signaling pathways related to metabolism and its immunological effects [69,70]. Most of these effects are

Fig. 3. Structure and signaling pathways of adiponectin via adiponectin receptors [113,114]. Adiponectin monomers have four domains which, as shown schematically, form four different isoforms upon post-translational modifications (Adiponectin can directly or indirectly activate (arrowheads) or inactivate (blunt ends) a series of signaling pathways through AdipoR1/2.

mediated by AMP-activated protein kinase (AMPK), in which AMPK induces anticancer, apoptotic, and growth arrest activity by increasing the expression of P21 and P53 and inhibiting mTOR activity [71–75]. Other effects of adiponectin include phosphoinoditide-Kinase (PI3K)/ Akt (which has anti-AMPK effects) [74,76], c-Jun N-terminal kinase (cJNK) (adiponectin enhances cJNK activity and activates caspase 3, 8, and 9, apoptosis) [77,78], signal transducer and activator of transcription 3 (STAT-3) [79], sphingolipids (adiponectin increases the activity of the ceramidase, thus converting ceramidase to SIP, which itself enhances cell proliferation and anti-apoptotic metabolites), WNT (adiponectin inhibits WNT signaling, which inhibits the negative effects on cellular growth and proliferation), and nuclear factor kappa-lightchain-enhancer of activated B cells (NF-κB) signaling [80–82]. These signaling pathways are summarized in Fig. 3. Adiponectin that is 4

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or cleaved globular, reduced significantly compared to control mice. However, because of upregulation of endopeptidase furin (endopeptidase cleavage adipolin at Lys generates a cleaved globular gCTRP12 isoform.), in the adipose tissue, the cleaved isoform of adipolin increased proportionately more than the total cleaved adipolin [91] (Fig. 4). Adipolin similar to adiponectin is significantly reduced in the circulation of obese mice, and also adipolin improves insulin sensitivity, inflammation and glucose tolerance [102,103]. The studies on lipid tissue in pre-pubertal children and in women with polycystic ovary syndrome show that the expression of the FAM132A gene and the level of adipolin in adipocytes have been reduced. However, studies concerning adipolin in animal models are significantly more frequent than in humans; thus, there information about humans is limited [98]. Adipolin, like adiponectin, reduces both the FAM132A expression in 3T3-L1 adipocytes in vitro and the simulation of endoplasmic reticulum stress. 3T3-L1 adipocytes reduces the amount of adipolin expression in exposure to risk factors and inflammation [103]. Adipolin has a close relationship with obesity and type 2 diabetes (T2DM) and significantly improves insulin and glucose tolerance in fat diet-induced obese (DIO) mice [104]. Insulin resistance and obesity occur in the presence of proinflammatory cytokines, which is commonly associated with chronic inflammation. With an anti-inflammatory role, adipolin is suggested to reduce the risk of proinflammatory cytokines and thus counteracts the resistance of insulin and obesity. In an earlier study, Wei et al. observed a rise in adipolin levels upon the injection of recombinant adipolin. They also observed adenovirus-mediated expression in wild type DIO and leptin-deficient mice. Upon this increase, insulin sensitivity enhanced and glucose tolerance improved [98]. Adipolin is involved in insulin signaling by increasing the phosphorylation of proteins such as MAPK, Akt, and IRS. Adipolin administration also downregulates enzymes such as glucose-6-phosphatase that acts on the liver gluconeogenesis and substantially increases in PI3K-dependent insulin signaling. Another study suggests that the insulin-resistant individuals increase resistin expression (an inflammatory factor) and reduce adipolin levels in these individuals. Studies have shown that the expression of adipolin decreases in human primary adipose tissue treatment with glucose, and is also regulated in adipolin in DIO mice. Decreased chronic inflammation is associated with increased levels of proprotein convertase and furin in DIO mice [97,104]. Consequently, the increase in the cleaved globular gCTRP12 due to the upregulation of furin in obese mice presumably makes insulin signaling to be less affected (compared to the full length fCTRP12) and hence, decreased insulin sensitivity [97]. As an endopeptidase, furin activates the TNF-α converting enzyme (TACE). Thus, furin-activated TACE processes and releases TNF-α. Therefore, if furin levels are increased, the amount of activated TACE is also increased, resulting in the reduction of adiponectin and adipolin levels as insulin-sensitive adipokines and hence chronic inflammation [105]. It is possible that in obese people, the fat mass is related to the level of the hormones produced by the adipose tissue, as the downregulated fat-derived hormones are the cause of increase in fat mass. Although adipolin-related signaling pathways have been widely studied, only a little information is available about adipolin level control [106,107]. One of these studies was performed to control the expression of the FAM132A and the new control paths proposed by Bell-Anderson et al. [108]. In this study, mice lacking transcriptional repressor Krüppel-like Factor 3 (KLF3/BKLF) reduce obesity, and the lack of KLF3 in high-fat diet mice can lead to resistance to obesity, insulin sensitivity, and glucose tolerance [108–110]. It is important that the levels of adipolin significantly increase in mice lacking KLF3 by limiting and regulating the FAM132A promoter [108]. Klf 3 is known as a transcriptional inhibitor. It includes a dominant N-terminal inhibitor that binds to CTBP (cellular protein, which binds

produced and released in both adipose and other tissues plays an important role in metabolic, inflammatory and multiple biological functions [83,84]. Recently, C1q/tumor necrosis factor-related proteins (CTRPs) have been identified as novel adipokines and among other types of adiponectin paralogs [85]. Adiponectin is a member of the C1q/TNF-related protein (CTRP) family mainly expressed in the adipose tissue [86,87]. C1q/TNF-related proteins (CTRPs) are family members with many specifications, such as metabolic function and cardiovascular disease under conditions of over-nutrition. These include conserved collagen tail domain and globular C1q-like domain at the C terminus region. Increased CTRP production under conditions obesity leads to many types of cardiovascular disease [87–89]. CTRP3 is reduced in progression of obesity-related cardiovascular disease; on the other hand, CTRP3 improves glucose metabolism by suppressing gluconeogenesis and activating AKT signaling [90,91]. CTRP9 has a very similar sequence of adiponectin. However, CTRP9 with an AMP-dependent mechanism can have cardiac damage after ischemia and can affect endothelial function and thus affect glucose metabolism in obese mice [92–94]. CTRP5 and CTRP13 lead to increased glucose uptake. AMPK signaling and glucose regulation are induced by CTRP13 [95,96]. Recently, a new adipocytokine has been identified, namely, C1q domain-containing protein 2/C1q/TNF-related protein 12 (C1qdc2/ CTRP12), which is insulin sensitive and expressed abundantly in adipose tissue. C1qdc2/CTRP12 decreases along with increased obesity and is referred to as adipolin (adipose-derived insulin-sensitizing factor) [97]. 1.4. Adipolin As a conserved adiponectin paralog, adipolin is a family of CTRP proteins and the minimum homology of adiponectin among other CTRPs [97]. The newly discovered adipolin is encoded by the FAM132A/CTRP12 gene. This adipokine is a type of hormone secreted from adipose cells and contributes to glycaemic control and insulin sensitivity [98]. The mouse model of diet-induced obesity using the systemic adipolin reduces macrophage infiltration and reduces adipocytokines. Moreover, the inflammatory proteins in the adipose tissue improves insulin resistance. If the cultured medium of adipolin-expressing cells is added to cultured macrophages, the pro-inflammatory mediators induced by inflammation will be suppressed. Therefore, adipolin plays an anti-inflammatory role and increases insulin sensitivity, can consequently be used to improve insulin resistance [96,99]. Adipolin has four distinct domains including 1) peptide signal (SP), 2) N-terminal domains with three N-glycosylation sites conforming to the NX motif, one CYS remainder, and polybasic cleavage motif KKXR, 3) collagen domains with six repetitions of GXY, and 4) a domain similar to the C1q globular in the C-terminal region, which has two Nglycosylation sites and three CYS residues [98,100] (Fig. 4). The significant point is that this protein may undergo several types of posttranslational changes. (See Fig. 5.) However, only four remaining CYS (three in the domains like C1q Globular and one in the N-terminal domain), the cleavage motif of the KKXR in the N-terminal domain, and one N-glycosylation site are conserved among various vertebrate species (Fig. 4). This protein can, be cleaved physiologically by the endopeptidase furin into two different isoforms in size, both of which circulate in human and mouse serum. These two isoforms have different functions and include full length fCTRP12 (40 kDa) and a cleaved gCTRP12 (25 kDa) (cleaved gCTRP12 is the predominant isoform in humans and plasma in mice) [98]. Studies on 3T3-L1 adipocytes cells and H4IIE hepatocytes show that full length fCTRP12 and cleaved gCTRP12 strongly activate AKT signaling and MAPkinase, respectively [101]. These studies also show that only full length fCTRP12 improves the uptake of insulin-stimulated glucose in the adipose tissue [97]. In diet-induced obese mice, all types of adipolins, either full-length 5

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Fig. 4. Domain structure and regulation of adipolin-dependent signaling pathways [97]. The furin enzyme can cleave between lysine and serine in polybasic motif KKSR in the N-terminal domain of adipolin, which results in the formation of the cleaved gCTRP12 isoform. Cleaved gCTRP12 isoform adipolin and full-length protein adipolin each prefers a particular signaling pathway; for example, full-length protein prefers to activate AKT signaling, while cleaved gCTRP12 isoform prefers to activate the p44/42 and p38 MAPK signaling.

adipose tissue exposed to metformin (an anti-diabetic drug), whereby adipolin was secreted from these cells. It is very important that the redox state of the cell regulate KLF3 and AMPK activities [103]. anti-inflammatory cytokines such as TNF-a and IL-6 significantly reduce the expression of adipolin when exposed to cultured adipocytes, indicating the association between obesity and chronic low-grade inflammation in adipose tissue [103]. Another study has shown that adipolin transcriptional levels in adipocytes increase when exposed to KLF15 (as a positive transcriptional regulator). Exposure of adipocytes with TNF-α or fatty tissue of obese mice significantly reduce the expression of KLF15, which suggests that fat-induced fatty tissue inflammation may reduce the expression of KLF15 [103]. In contrast to KLF3, KLF15 regulates the expression of adipolin positively, and reduces the expression of adipolin by decreasing KLF15. Therefore, it is possible to use KLF15 and KLF3 as targets for adipolin

to a Pro-X-Asp-Leu-Ser motif in the C-terminus). CTBP is activated with NADH [111,112] and is a metabolic sensor that can modulate the expression of the gene in response to the redox state. Activating this pathway is possibly a kind of cellular response to intracellular energy levels and metabolic processes. Many studies have been conducted on KLF3 null mice. KLF3, as a transcription regulator, regulates adipogenesis in vitro. As a result, KLF3 null mice are lean and resistant to glucose intolerance and obesity. KLF3 reduces adipolin levels by binding to the FAM132A promoter and inhibiting promoter activity and thus inhibiting FAM132A expression [104]. Therefore, in KLF3 null mice, the promoter of FAM132A is activated and the amount of produced adipolin levels is greater than its wild type, which increases the amount of adipolin via targeting KLF3 as a new therapeutic method for insulin resistance. It is important to know that the expression of adipolin and its secretion may not be simultaneous. In another study, the AMPK signaling pathway was activated in the human subcutaneous 6

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anti-inflammatory phenotype: 1) Adiponectin can reduce the expression of markers involved in the activation of NF-κB including TNF-α, IL-6 and inducible nitric oxide synthase (iNOS). 2) Adiponectin induces expression of M2 macrophage markers that include arginese-1 (Arg-1), IL-10, and mannose receptor (MR). 3) Adiponectin induces the phagocytosis of the cells associated with M2 phenotype macrophages in the early apoptotic cells [103]. Collectively, all of these data indicate that high levels of adiponectin and adipolin can lead to anti-inflammatory phenotype in macrophages and have beneficial effects on glucose tolerance and insulin sensitivity [124]. Adipolin and adiponectin can protect the body against obesityrelated diseases by regulating macrophages [103]. 2. Conclusion Fig. 5. Effects of adiponectin and adipolin on macrophage function and phenotype [118,127,128].

Obesity and risk factors associated with obesity, such as insulin resistance and arteriosclerosis, are rising among people. It has been continually more recognized that the increase of obesity-related disorders, such as atherosclerosis, is closely related to the imbalance of anti-inflammatory hormones. Dysregulation in anti-inflammatory adipokines is caused by fat accumulation, leading to the development or progression of metabolic and cardiovascular disorders. Obviously, adiponectin is an adipocyte-derived hormone that has various functions in different tissues, such as the heart and vessels. Understanding the mechanisms involved in accumulation, efflux and esterification of cholesterol from macrophages is significantly important for arteriosclerosis diagnosis and treatment. When atherogenesis occurs, there will be a decreased expression of the protein-encoding genes that contribute to cholesterol efflux from macrophages (such as ABCA1, ABCG1 and SR-BI). Also, the expression of genes that encode proteins involved in ox-LDL internalization is increased by macrophages (such as CD36 and SR-A). These events result in CE accumulation in macrophages and the formation of foam cells. Adipolin is a newly identified adipocytokine that improves glucose metabolism and insulin sensitivity [125]. A recent study shows that the full (not cleaved) form of adipoline promotes glucose uptake in adipocytes when stimulated by insulin [101]. The full and cleaved forms of adipoline show different impacts on insulin sensitivity in vivo. The full form decreases in obesity and thus insulin resistance increases by suppressing the full form of adipolin. Relevant information about the cleaved adipolin isoform is not yet sufficient and requires further research. TNFa is an adipocytokine associated with insulin resistance in obesity [126]. The active and cleaved TNFa from increases in the adipose tissue when TNFa converting enzyme (TACE) is activated. To link between obesity and metabolic disorders such as diabetes, heart disease and cancers, we need to have a fundamental understanding of insulin resistance-based molecular mechanisms and the role and function of adipokines such as adiponectin and adipolin. However, adipokines plays an important role in improving insulin sensitivity, and accordingly they can prove promising for cardiovascular disease treatment.

manipulation [108]. 1.5. Functional regulation of macrophage foam cells by adiponectin and adipolin Adiponectin and adipolin are contributory to health promotion [103]. The higher the body fat stores, the lower the level of adiponectin and adipoline [115]. Adiponectin and adipolin as protein hormones are released substantially in the adipose tissue [103,114]. They are also involved in glucose homeostasis and oxidation of fatty acids [115,116]. Subcutaneous adipoline is of a higher amount than the adipoline in visceral tissue depots [103]. These hormones modulate the anti-inflammatory function by adjusting the function of the macrophages. Atherosclerosis lesion progression is achieved by the accumulation of lipid-laden foam cells and their inflammation. Given their anti-inflammatory effects, adiponectin and adipolin prevent the formation of macrophage cells into foam cells, possibly through the expression of class A scavenger receptor (SR-A) in human macrophages [117] [117] Subsequently, the amount of intracellular cholesteryl ester in macrophage cells is reduced [117]. Adiponectin and adipolin lead to reduced expression and production of lipopolysaccharide (LPS)-stimulated TNF-α in macrophages [103,118,119]. The expression of adipolin is increased by insulin and rosiglitazone, without any change in adipolin receptors [120]. Adipolin mRNA and its proteins are reduced in blood circulation of obese mice. Systematic administration of adipolin for these mice reduces adipose tissue macrophage (ATM) infiltration and the expression of pro-inflammatory gene in the adipose deposite [103]. Adiponectin inhibits the activity of TNF-α (through Toll-like receptor) and stimulates IL-10 expression (an anti-inflammatory cytokine) in mice's macrophages [121]. Moreover, adiponectin alters the polarization of the macrophages towards the anti-inflammatory phenotype [122]. Macrophages that infiltrate adipose tissue of adult mature mice mainly express the genes of M1 or “classically activated” macrophage, and the macrophages that infiltrate the adipose tissue of lean mice express and indicate the M2 “alternatively activated” macrophages [123]. Stimulation with recombinant adiponectin proteins leads to increased levels of M2 markers and reduced production of reactive oxygen species (ROS) in cultivated macrophages. Adiponectin can act as a macrophage polarization regulator [124]. Overall, it can be argued that adiponectin can inhibit the transmission of macrophage to foam cells by inhibiting SR-A expression. Based on M1 and M2 macrophage phenotypes, adiponectin has three basic roles whereby it can direct polarization of macrophages towards

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