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Clinica Chimica Acta
journal homepage: www.elsevier.com/locate/clinchim
Invited critical review
Foam cells in atherosclerosis^
Xiao-hua Yu a, Yu-chang Fuc, Da-Wei Zhang d, Kai Yin Chao-ke Tang a'b'**
a Life Science Research Center, University of South China, Hengyang, Hunan 421001, China
b 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
article info
abstract
Article history:
Received 25 April 2013
Received in revised form 4 June 2013
Accepted 6 June 2013
Available online xxxx
Keywords:
Macrophages
Foam cells
Atherosclerosis is a chronic disease characterized by the deposition of excessive cholesterol in the arterial intima. 28 Macrophage foam cells play a critical role in the occurrence and development of atherosclerosis. The generation of 29 these cells is associated with imbalance of cholesterol influx, esterification and efflux. CD36 and scavenger receptor 30 class A (SR-A) are mainly responsible for uptake of lipoprotein-derived cholesterol by macrophages. Acyl coen- 31 zyme A:cholesterol acyltransferase-1 (ACAT1) and neutral cholesteryl ester hydrolase (nCEH) regulate cholesterol 32 esterification. ATP-binding cassette transporters A1(ABCA1),ABCG1 and scavenger receptor BI (SR-BI) play crucial 33 roles in macrophage cholesterol export. When inflow and esterification of cholesterol increase and/or its outflow 34 decrease, the macrophages are ultimately transformed into lipid-laden foam cells, the prototypical cells in the 35 atherosclerotic plaque. The aim of this review is to describe what is known about the mechanisms of cholesterol 36 uptake, esterification and release in macrophages. An increased understanding of the process of macrophage 37 foam cell formation will help to develop novel therapeutic interventions for atherosclerosis. 38
© 2013 The Authors. Published by Elsevier B.V. All rights reserved. 39
Contents
1. Introduction .............................................................. 0
2. Cholesterol uptake ........................................................... 0
2.1. CD36 .............................................................. 0
2.2. SR-A............................................................... 0
3. Cholesterol esterification......................................................... 0
3.1. ACAT1.............................................................. 0
3.2. nCEH .............................................................. 0
4. Cholesterol efflux............................................................ 0
4.1. ABCA1.............................................................. 0
4.2. ABCG1.............................................................. 0
4.3. SR-BI .............................................................. 0
5. Conclusion and future directions..................................................... 0
Acknowledgment............................................................... 0
References.................................................................. 0
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-y, peroxisome proliferator-activated receptor-y; ERK1/2, extracellular signal-regulated kinases 1 and 2; PPREs, PPAR response elements; PKB, protein kinase B; PKC, protein kinase C; TGF-p, transforming growth factor-p; 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: kaiyinby@yahoo.com.cn (K. Yin), tchaoke@yahoo.com.cn (C. Tang).
0009-8981/$ - see front matter © 2013 The Authors. Published by Elsevier B.V. All rights reserved. http://dx.doi.org/! 0.1016/j.cca.2013.06.006
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1. Introduction
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-B[ (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.
2. Cholesterol uptake
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.
2.1. CD36
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
as a high-affinity receptor for ox-LDL. A domain located between 93 amino acids 155 and 183 of CD36 involves in ox-LDL binding. Other 94 ox-LDL binding sites have also been reported such as amino acids 95 28-93 and possibly 120-155. Binding of ox-LDL to CD36 leads to 96 endocytosis through a lipid raft pathway that is distinct from the 97 clathrin-mediated or caveolin internalization pathways. The patho- 98 genic role of ox-LDL in atherosclerosis largely depends on CD36. A 99 recent study revealed that plasma soluble CD36 correlates significant- 100 ly with markers of atherosclerosis, insulin resistance and fatty liver in 101 a nondiabetic healthy population [5]. Patients with acute coronary 102 syndromes exhibit a significant increase in CD36 expression in circu- 103 lating monocytes, which can be inhibited by a 6-month treatment of 104 atorvastatin [6]. Small molecules with anti-CD36 activity have been 105 shown to decrease postprandial hyperlipidemia and protect against 106 atherosclerosis [7]. In addition, the 573A allele of CD36 has a protec- 107 tive effect against atherosclerosis development while the 591T allele 108 is a cardiovascular risk factor [8]. On the other hand, Moore and col- 109 leagues reported that apoE-/- mice lacking CD36 or SR-A display in- 110 creased aortic sinus atherosclerotic lesion area and abundant 111 macrophage foam cells in the aortic intima despite reductions in peri- 112 toneal macrophage CE accumulation in vivo [9]. Moreover, clinical 113 studies show that patients with CD36 deficiency are associated with 114 severe and enhanced atherosclerotic diseases [10]. Therefore, the 115 role of CD36 as a proatherogenic mediator of ox-LDL uptake in vivo 116 needs to be reassessed. 117
CD36 is highly expressed in macrophages and its expression is regu- 118 lated by multiple factors (Fig. 1). Recently, Inoue et al. reported that 119 astaxanthin (ASX), an oxygenated carotenoid (xanthophyll), signifi- 120 cantly increases CD36 levels in peritoneal macrophages by stimulating 121 peroxisome proliferator-activated receptor-Y (PPARy) [11]. On the 122 other hand, curcumin, a potent antioxidant extracted from Curcuma 123 longa, induces a PPARY-independent CD36 overexpression through 124 upregulating nuclear erythroid-related factor 2(Nrf2) [12]. Additionally, 125 Gao et al. reported that palmitate increases CD36 expression in mono- 126 cytes through the regulation of de novo ceramide synthesis [13]. Sup- 127 plementation of the mushroom Agaricus blazei for 12 weeks markedly 128 elevates CD36 expression and plaque vulnerability in apoE-/- mice, 129
Quercitrin
Berberine
e^o t№q 1 1 1 11
Kaempferol Palmitate fTSIIA ASX
JSqualene Walnut
I i I I I
Curcumin
Fig. 1. Regulation of CD36 and SR-A expression in macrophages. CD36 expression is induced by ASX and inhibited by TSIIA and quercitrin via PPARy 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-a enhance SR-A levels, whereas MLPE and H2S diminish its levels. RXR: retinoid X receptor.
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130 indicating a proatherogenic property of mushroom A. blazei [14]. In
131 contrast, a dietary compound quercitrin inhibits CD36 expression in
132 murine macrophages through interfering with PKC/PPARy signaling
133 cascades [15]. Tanshinone IIA (TSIIA), a lipophilic diterpene isolated
134 from Salvia miltiorrhiza Bunge (Danshen), also decreases CD36 levels
135 in ox-LDL treated macrophages by antagonism of PPARy [16]. Similarly,
136 endomorphin-1(EM-1), a member of the endogenous opioid peptides
137 family, and squalene, one of the components of olive oil, downregulate
138 CD36 expression and prevent lipid accumulation in human lipid-laden
139 macrophages [17,18]. Treatment of macrophages with kaempferol
140 inhibits c-Jun/activator protein-1 (AP-1) nuclear translocation and
141 leads to the downregulation ofCD36 expression [19]. Atheroprotective
142 effect of dietary intake of walnut that enriches in n-3 polyunsaturated
143 fatty acids and antioxidant compounds, is associated with reduced
144 CD36 expression in apoE-/- mice [20]. In addition, the combined treat-
145 ment of interferon y and tumor necrosis factor a (TNF-a) significantly
146 reduces CD36 levels [21]. Thus, these factors may act as novel modula-
147 tors for macrophage-to-foam cell transformation.
3. Cholesterol esterification 193
In addition to cholesterol uptake, the balance of free cholesterol 194 (FC) and CE is also critical for the regulation of intracellular cholester- 195 ol content in macrophage foam cells. After internalization, lipopro- 196 teins are delivered to the late endosome/lysosome, where CE is 197 hydrolyzed into FC by lysosomal acid lipase (LAL). To prevent the 198 FC-associated cell toxicity, the FC released is re-esterified on the en- 199 doplasmic reticulum (ER) by ACAT1 and stored in cytoplasmic lipid 200 droplets. If this persistently occurs, excessive CE will accumulate in 201 macrophages, thereby resulting in the formation of foam cells. 202 These cells are often referred to as foam cells because of their charac- 203 teristic "foamy" appearance. The resulting CE are hydrolyzed by nCEH 204 to release FC for transporters-mediated efflux, which is increasingly 205 being recognized as the rate-limiting step in FC outflow [31]. Thus, 206 the cycle of esterification and hydrolysis of CE is one of the key 207 steps in maintaining intracellular cholesterol homeostasis, and 208 ACAT1 and nCEH play a crucial role in the process. 209
148 2.2. SR-A
149 SR-A, a 77-kDa cell surface glycoprotein, is a member of class A SR
150 family. The human and murine SR-A genes are located on chromo-
151 some 8 and can be transcribed to produce three (SR-AI/II/III) and
152 two SR-A splice variants, respectively. SR-A is highly expressed in
153 macrophages and mediates the uptake of ox-LDL into macrophages.
154 Inhibition of SR-A in macrophages significantly ameliorates foam
155 cell formation and atherosclerosis in apoE-/- mice [22]. Silencing
156 of SR-A or CD36 alone reduces atherogenesis in LDL receptor
157 (LDLR)-deficient apolipoprotein B100 mice, whereas simultaneous
158 silencing of both receptors has no beneficial effect, suggesting that
159 the compensatory upregulation of the two receptors is sufficient for
160 the uptake of modified LDL [23]. Conversely, completely knockout of
161 SR-A alone aggravates atherosclerosis despite of reduced peritoneal
162 macrophage lipid accumulation [9], but combined deletion of SR-A
163 and CD36 reduces atherosclerotic lesion complexity without affecting
164 foam cell formation in hyperlipidemic mice, indicating that specific
165 inhibition of these pathways in vivo may promote plaque stability
166 [24]. Thus, further studies are necessary to clarify the role of SR-A in
167 atherosclerosis.
168 The expression level of SR-A is upregulated by a variety of agents
169 (Fig. 1). Treatment of ox-LDL stimulates SR-A expression and pro-
170 motes the uptake of ox-LDL into macrophages. Li and colleagues
171 reported that berberine significantly elevates mRNA and protein
172 levels of SR-A in mouse RAW264.7 cells through inhibiting PTEN ex-
173 pression and sustaining Akt activation [25]. Proinflammatory cyto-
174 kines such as TNF-a also induce SR-A expression but via
175 suppression of nuclear factor-KB (NF-kB) signaling [26]. More recent-
176 ly, voltage-gated potassium channel Kv1.3 has been shown to
177 upregulate SR-A expression in human monocyte-derived macro-
178 phages, revealing that specific Kv1.3 blockade may represent a
179 novel strategy to modulate cholesterol metabolism in macrophages
180 [27]. Taken together, these findings indicate that inhibition of these
181 agents may reduce the uptake of ox-LDL by macrophages and then
182 prevent the formation of foam cells.
183 Hydrogen sulfide (H2S), curcumin and mulberry leaf polyphenolic
184 extracts (MLPE) have been reported to decrease SR-A expression
185 (Fig. 1). Our previous studies have shown that H2S reduces SR-A ex-
186 pression and foam cell formation in human monocyte-derived macro-
187 phages via the K(ATP)/ERK1/2 pathway [28]. Curcumin decreases
188 SR-A protein levels in macrophages through the ubiquitin/proteasome
189 system(UPS)-dependent proteolysis [29]. On the other hand, MLPE
190 inhibits PPARy and then reduces macrophage SR-A levels, suggesting
191 a protective role of MLPE in regulating intracellular lipid homeostasis
192 within the intima [30].
3.1.ACAT1 210
ACAT1 is an integral membrane protein that converts FC into the 211 storage form of CE. It has already been reported that ACAT1 deficiency 212 increases the synthesis and efflux of FC in mouse peritoneal macro- 213 phages while its overexpression promotes CE accumulation and 214 macrophage-derived foam cell formation [32,33]. However, the role 215 of ACAT1 in atherosclerosis is currently under debate. Kusunoki et 216 al. revealed that ACAT1 inhibition attenuates atherosclerosis in apoE 217 mice [34]. On the other hand, mice lacking macrophage-derived 218 ACAT1 show accelerated atherosclerosis [35,36]. This may be due to 219 the cytotoxic effects of increased FC levels, which crystallize in mac- 220 rophage foam cells. The formation of cholesterol crystals not only 221 destroys cholesterol metabolism during the development of athero- 222 sclerosis, but also facilitates the secretion of inflammatory mediators 223 such as IL-1p and IL-18 [37]. Taken together, the effects of ACAT1 on 224 atherosclerosis remain to be further investigated. 225
Numerous steps have been implicated in the modulation of ACAT1 226 expression (Fig. 2). Insulin has been shown to enhance ACAT1 expres- 227 sion in THP-1 macrophages via MAP kinases (MAPK)/CCAAT/enhanc- 228 er binding protein a(C/EBPa) signaling pathway [38]. Yang et al. 229 observed that voltage-gated potassium channel Kv1.3 significantly 230 upregulates ACAT1 expression and increases percentage of CE in 231 human monocyte-derived macrophages exposed to ox-LDL [27]. 232 Chlamydia pneumoniae (C. pneumoniae) infection is reported to in- 233 crease ACAT1 expression and disturb cholesterol homeostasis 234 through c-Jun NH(2) terminal kinase (JNK)/PPARy dependent signal 235 transduction pathways [39]. Leptin, an adipose tissue-derived hor- 236 mone, accelerates CE accumulation in human monocyte-derived mac- 237 rophages by increasing ACAT1 expression via Janus-activated kinase 2 238 (JAK2) and PI3K [40]. In contrast, treatment of cultured THP-1 macro- 239 phages in vitro with an angiotensin receptor blocker, candesartan, 240 leads to a decrease in ACAT1 expression [41]. Incretins such as 241 glucagon-like peptide-1 (GLP-1) and glucose-dependent insulino- 242 tropic polypeptide (GIP) are also able to decrease the levels of 243 ACAT1 by cAMP activation [42]. Our recent studies showed that H2S 244 inhibits macrophage foam cell formation by suppressing ACAT1 ex- 245 pression via K(ATP)/ERK1/2 pathway [28]. Additionally, ghrelin, an 246 endogenous ligand of the growth hormone secretagogue receptor 247 (GHS-R), lowers the expression of ACAT1 in THP-1 macrophages via 248 pathways involving GHS-R and PPARy, indicating a protective role 249 for ghrelin in controlling cellular lipid accumulation [43]. 250
3.2. nCEH 251
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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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.
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 intra-cellular 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 1L-1 cytokine family, also reduces nCEH mRNA levels in primary human monocyte-derived macrophages by activating ST-2/NF-kB signaling pathway [50,51]. Variety of other factors that can regulate nCEH expression will be probably found in later researches.
4. Cholesterol efflux
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
apolipoprotein A-I (apoA-1). Active transport via transporters includ- 291
ing the best characterized ABCA1, ABCG1 and SR-BI is mainly respon- 292
sible for the bulk efflux of cholesterol from macrophages onto 293
extracellular acceptors. 294
4.1.ABCA1 295
ABCA1 is a member of the large superfamily of ABC transporters. It is 296
now well established that ABCA1 plays a critical role in the prevention 297
of macrophage foam cell formation and atherosclerosis by mediating 298
the active transport of intracellular cholesterol and phospholipids to 299
apoA-1, the major lipoprotein in HDL. Bochem and colleagues have dem- 300
onstrated that ABCA1 mutation carriers show lower HDL-cholesterol 301
(HDL-C) levels and a larger atherosclerotic burden compared with con- 302
trols [52]. Unexpectedly, mice lacking ABCA1 and SR-BI display severe 303
hypocholesterolemia and foam cell accumulation, but have no athero- 304
sclerosis, which is mainly due to the absence of proatherogenic lipopro- 305
teins [53]. ABCA1 overexpression in the liver of LDLR-/- mice results in 306
accumulation of proatherogenic lipoproteins and enhanced atheroscle- 307
rosis [54]. Thus, in regard to these contradictory observations, a careful 308
re-evaluation of ABCA1 as a potent antiatherogenic agent is necessary. 309
The expression of ABCA1 is highly regulated by multiple processes 310 (Fig. 3). Lee et al. observed that quercetin stimulates PPAR^/liver X 311
receptor a (LXRa) signaling and then increases ABCA1 expression 312
and cholesterol efflux from THP-1 macrophages, indicating that in- 313 gestion of quercetin or quercetin-rich foods may be an effective way 314 to lower the risks of atherosclerosis [55]. Studies from our laboratory 315
showed that apelin-13, a recently discovered adipocytokine, en- 316
hances ABCA1 expression in THP-1 macrophage-derived foam cells 317
via activating the PKCa pathway and inhibiting calpain activity [56]. 318
Toll-like receptor 2 (TLR2) agonist Pam(3)CSK(4) raises ABCA1 levels 319
in RAW 264.7 macrophages via activation of PKC-n/phospholipase D2 320 (PLD2) signaling pathway [57]. S-allylcysteine, the most abundant 321
organosulfur compound in aged garlic extract, also elevates ABCA1 322
content in human THP-1 macrophages [58]. On the other hand, unsat- 323
urated fatty acids suppress ABCA1 expression in RAW 264.7 macro- 324
phages by two distinct mechanisms: LXR-dependent transcriptional 325
repression possibly through modulating histone acetylation states, 326
and LXR-independent posttranslational inhibition [59]. Our previous 327
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Apelin-13 1 l P3m(3)CSK(4)
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.
328 studies indicate that IL-18 and IL-12 synergistically decrease ABCA1
329 levels in THP-1 macrophage-derived foam cells through the IL-18 re-
330 ceptor (IL-18R)/NF-KB/zinc finger protein 202 (ZNF202) signaling
331 pathway [60]. In addition, miR-26 prevents ABCA1 expression and
332 subsequent cholesterol efflux from macrophages to apoA-I via
333 targeting LXRa, indicating a novel regulatory role of miR-26 in cellu-
334 lar lipid accumulation within the intima [61]. Thus, miR-26 inhibitors
335 can be potentially used to treat atherosclerosis.
336 4.2. ABCG1
[69]. Protocatechuic acid (PCA), a gut microbiota metabolite of 361 cyanidin-3 to 0-(3-glucoside, exerts an antiatherogenic effect partially 362 through inhibition of miR-10b-mediated downregulation of ABCG1 ex- 363 pression, indicating that gut microbiota is a potential novel target for pre- 364 vention and treatment of atherosclerosis [70]. Conversely, subclinical 365 low-dose lipopolysaccharide (LPS) potently reduces the expression of 366 ABCG1 in bone marrow-derived macrophages through interleukin-1 367 receptor-associated kinase 1(IRAK-1)/glycogen synthase kinase 3(3 368 (GSK3()/retinoic acid receptor a (RARa) signaling pathway, revealing 369 a novel intracellular network regulated by low-dose endotoxemia [71]. 370
337 ABCG1 mediates cholesterol removal from macrophages to HDL
338 particles but not to lipid-free apoA-I. It has been shown that a func-
339 tional genetic variant in the ABCG1 promoter is associated with an
340 increased risk of myocardial infarction and ischemic heart disease in
341 the general population [62]. Lack of macrophage ABCG1 has been
342 reported to cause a modest increase in atherosclerotic lesions [63].
343 However, two other independent groups reported that LDLR-/-
344 mice lacking macrophage ABCG1 show decreased atherosclerotic
345 lesions [64,65]. Most recently, Meurs and colleagues found that the
346 absence of ABCG1 leads to increased lesions in early stage of athero-
347 sclerosis but causes retarded lesion progression in more advanced
348 stage of atherosclerosis in LDLR-/- mice, suggesting that the influ-
349 ence of ABCG1 deficiency on lesion development depends on the
350 stage of atherogenesis [66]. Therefore, the impact of ABCG1 on the
351 development of atherosclerosis is complex and needs to be further
352 investigated.
353 The regulation of ABCG1 expression has similarities with that of
354 ABCA1, consistent with a shared role in cholesterol export (Fig. 3).
355 Cineole, a small aroma compound in teas and herbs, induces ABCG1 ex-
356 pression in macrophages through the activation of LXR [67]. Fucosterol,
357 a sterol that is abundant in marine algae, is also able to increase ABCG1
358 levels in a LXR-dependent mechanism [68]. Consumption of extra-
359 virgin olive oil (EVOO) for 12 weeks induces a concentration-
360 dependent upregulation of ABCG1 expression in human macrophages
4.3. SR-BI 371
SR-BI promotes cholesterol efflux from macrophages to HDL. A 372 genetic variant of the SR-BI in humans leads to a reduction in choles- 373 terol efflux from macrophages but has no significant increase in ath- 374 erosclerosis [72]. On the other hand, inactivation of macrophage 375 SR-BI facilitates atherosclerotic lesion development in apoE-/- mice 376
[73]. However, a recent report suggests that the presence of macro- 377 phage SR-BI inhibits advanced atherosclerotic lesion but promotes 378 early lesion development in LDLR-/- mice, indicating a unique dual 379 role for macrophage SR-BI in the pathogenesis of atherosclerosis 380
[74]. SR-BI is also highly expressed in the liver. Hepatic SR-BI expres- 381 sion is a positive regulator of the rate of RCT from macrophages to the 382 liver, bile, and feces. Of note, inhibition of hepatic SR-BI using RNA in- 383 terference technique reduces atherosclerosis in rabbits fed with 384 cholesterol-rich diet, indicating that the effect of SR-BI on atherogen- 385 esis in rabbits is different from the one seen in rodents [75]. There- 386 fore, more studies are needed to elucidate the role of SR-BI in 387 regulating atherosclerosis. 388
Multiple factors regulate SR-BI expression (Fig. 3). Resveratrol 389 (Res), a bioactive molecule used in dietary supplements, and 390 13-hydroxy linoleic acid (LA), a natural PPAR agonist, induce SR-BI 391 expression in macrophages through PPAR^/LXRa pathway [76,77]. 392 Uto-Kondo et al. recently reported that coffee intake significantly 393
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394 increases SR-BI expression and HDL-mediated cholesterol efflux from
395 macrophages via its plasma phenolic acids [78]. Hydrogen administra-
396 tion also raises macrophage SR-BI levels in apoE-/- mice [79]. On the
397 other hand, pregnancy-associated plasma protein-A (PAPP-A), a
398 newly recognized metalloproteinase in the insulin-like growth factor
399 (IGF) system, significantly decreases SR-BI expression and promotes
400 the formation of macrophage foam cells via IGF-1/PI3K/Akt/LXRa
401 signaling pathway, indicating a novel mechanism for its proatherogenic
402 effect [80].
403 5. Conclusion and future directions
404 The balanced of cholesterol influx, esterification and release is nec-
405 essary to avoid lipid overload within macrophages, and ultimately,
406 atheroma development. Under atherogenic conditions, efflux of cho-
407 lesterol is decreased due to reduced expression of ABCA1, ABCG1
408 and SR-BI; however its uptake is increased due to enhanced expres-
409 sion of CD36 and SR-A as well as excess esterification of cholesterol oc-
410 curs because of higher ACAT1 level and lower nCEH level. This leads to
411 excessive CE accumulation as lipid droplets in macrophages, thereby
412 contributing to the formation of foam cells (Fig. 4). Therefore,
413 targeting these three pathways could be a viable approach to regulate
414 cholesterol metabolism in macrophages and treat atherosclerotic car-
415 diovascular diseases. K-604 and rimonabant, recently identified as po-
416 tent inhibitors of ACAT1, have been shown to inhibit macrophage
417 foam cell formation and retard atherosclerosis in apoE-/- mice Acknowledgment
418 [81,82]. A growing body of evidence indicates that food components
419 play an important role in prevention of foam cell formation by reduc-
420 ing cholesterol uptake and/or promoting its removal. For instance,
421 seven phenolic acids, the major bioactive compounds in blueberries,
have been recently reported to attenuate the formation of macro- 422
phage foam cells through downregulation of CD36 expression and 423
upregulation of ABCA1 expression [83]. Notably, despite strong 424
inverse association of plasma HDL levels with the risks of atheroscle- 425
rotic cardiovascular diseases, HDL-raising therapies are not always 426
effective. A randomized and placebo-controlled intervention trial has 427
demonstrated that niacin increases HDL-C but does not reduce cardio- 428
vascular events [84]. Moreover, a large human genetics study shows 429
that genetic variants that enhance HDL-C levels do not necessarily as- 430
sociate with myocardial infarction risk [85]. As a result, additional 431
studies are needed to evaluate the role of new compounds to raise 432
HDL-C levels or modify HDL composition and functionality. In addition 433
to these receptors, enzymes and transporters, we should pay attention 434
to the role of other molecules in cholesterol trafficking. In summary, 435
further work is required to elucidate the diverse processes that regu- 436
late the expression and activity of these proteins, and to determine 437
their contribution to disease protection in humans. These studies 438
will provide more insight into their physiological roles and will reveal 439
novel therapeutic strategies for treating atherosclerotic cardiovascular 440
disease. 441
Disclosure 443
The authors have declared no conflict of interest. 445
The authors gratefully acknowledge the financial support from 447 the National Natural Sciences Foundation of China (81070220 and 448 81170278), and Aid Program for Science and Technology Innovative 449
ox-LDL
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.
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Research Team in Higher Educational Institutions of Human Province, China (2008-244).
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