Clinica Chimica Acta 424 (2013) 245–252

Contents lists available at ScienceDirect

Clinica Chimica Acta

journal homepage: www.elsevier.com/locate/clinchim

Invited critical review

Foam cells in atherosclerosis

Xiao-Hua Yu a, Yu-Chang Fu c, Da-Wei Zhang d, Kai Yin b,⁎, 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

a r t i c l e i n f o a b s t r a c t

Article history: Atherosclerosis is a chronic disease characterized by the deposition of excessive cholesterol in the arterial intima.
Received 25 April 2013 Macrophage foam cells play a critical role in the occurrence and development of atherosclerosis. The generation of
Received in revised form 4 June 2013 these cells is associated with imbalance of cholesterol influx, esterification and efflux. CD36 and scavenger receptor
Accepted 6 June 2013
class A (SR-A) are mainly responsible for uptake of lipoprotein-derived cholesterol by macrophages. Acyl coen-
Available online 16 June 2013
zyme A:cholesterol acyltransferase-1 (ACAT1) and neutral cholesteryl ester hydrolase (nCEH) regulate cholesterol
Keywords:
esterification. ATP-binding cassette transporters A1(ABCA1), ABCG1 and scavenger receptor BI (SR-BI) play crucial
Foam cells roles in macrophage cholesterol export. When inflow and esterification of cholesterol increase and/or its outflow
Atherosclerosis decrease, the macrophages are ultimately transformed into lipid-laden foam cells, the prototypical cells in the
CD36 atherosclerotic plaque. The aim of this review is to describe what is known about the mechanisms of cholesterol
ACAT1 uptake, esterification and release in macrophages. An increased understanding of the process of macrophage
ABCA1 foam cell formation will help to develop novel therapeutic interventions for atherosclerosis.
ABCG1 © 2013 The Authors. Published by Elsevier B.V. Open access under CC BY-NC-ND license.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 246
2. Cholesterol uptake . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 246
2.1. CD36 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 246
2.2. SR-A . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 247
3. Cholesterol esterification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 247
3.1. ACAT1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 247
3.2. nCEH . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 247
4. Cholesterol efflux . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 248
4.1. ABCA1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 248
4.2. ABCG1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 249
4.3. SR-BI . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 249
5. Conclusion and future directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 250
Disclosure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 250
Acknowledgment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 250
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 251

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.

⁎ 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.-K. Tang).

0009-8981 © 2013 The Authors. Published by Elsevier B.V. Open access under CC BY-NC-ND license.
http://dx.doi.org/10.1016/j.cca.2013.06.006
246 X.-H. Yu et al. / Clinica Chimica Acta 424 (2013) 245–252
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), ex-
cessive 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 princi-
pal receptors responsible for the binding and uptake of ox-LDL in mac-
rophages [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 cho-
lesterol 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 macro-
phage foam cells.
2. Cholesterol uptake
Cholesterol uptake is a pathway by which extracellular modified
LDL are ingested by macrophages via receptors-mediated phagocyto-
sis 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 ac-
count 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
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.
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 patho-
genic role of ox-LDL in atherosclerosis largely depends on CD36. A
recent study revealed that plasma soluble CD36 correlates significant-
ly 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 circu-
lating 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 protec-
tive effect against atherosclerosis development while the 591T allele
is a cardiovascular risk factor [8]. On the other hand, Moore and col-
leagues reported that apoE−/− mice lacking CD36 or SR-A display
increased aortic sinus atherosclerotic lesion area and abundant mac-
rophage foam cells in the aortic intima despite reductions in peritone-
al 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 regu-
lated by multiple factors (Fig. 1). Recently, Inoue et al. reported that
astaxanthin (ASX), an oxygenated carotenoid (xanthophyll), signifi-
cantly 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 mono-
cytes through the regulation of de novo ceramide synthesis [13]. Sup-
plementation of the mushroom Agaricus blazei for 12 weeks markedly
elevates CD36 expression and plaque vulnerability in apoE−/− mice,
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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 treat-
ment of interferon γ and tumor necrosis factor α (TNF-α) significantly
reduces CD36 levels [21]. Thus, these factors may act as novel modula-
tors for macrophage-to-foam cell transformation.
2.2. SR-A
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 chromo-
some 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 sus-
taining 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 choles-
terol metabolism in macrophages [27]. Taken together, these find-
ings 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 ex-
pression and foam cell formation in human monocyte-derived macro-
phages 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].
247
3. Cholesterol esterification
In addition to cholesterol uptake, the balance of free cholesterol
(FC) and CE is also critical for the regulation of intracellular cholester-
ol content in macrophage foam cells. After internalization, lipopro-
teins 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 en-
doplasmic 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 charac-
teristic “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.
3.1. ACAT1
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 macro-
phages 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 mac-
rophage foam cells. The formation of cholesterol crystals not only
destroys cholesterol metabolism during the development of athero-
sclerosis, 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 expres-
sion in THP-1 macrophages via MAP kinases (MAPK)/CCAAT/enhanc-
er 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 hor-
mone, accelerates CE accumulation in human monocyte-derived mac-
rophages by increasing ACAT1 expression via Janus-activated kinase 2
(JAK2) and PI3K [40]. In contrast, treatment of cultured THP-1 macro-
phages 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 insulino-
tropic 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 ex-
pression 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].
3.2. nCEH
The esterification of FC into CE by ACAT1 is opposed by nCEH,
which hydrolyzes CE to cholesterol for efflux out of the cells. nCEH
248 X.-H. Yu et al. / Clinica Chimica Acta 424 (2013) 245–252
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 overex-
pression 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 athero-
sclerotic 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 sig-
naling 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 ves-
sel wall through transporters or other mechanisms such as passive
diffusion, and then collected by high-density lipoprotein (HDL) or
apolipoprotein A-I (apoA-I). Active transport via transporters includ-
ing the best characterized ABCA1, ABCG1 and SR-BI is mainly respon-
sible for the bulk efflux of cholesterol from macrophages onto
extracellular acceptors.
4.1. ABCA1
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 dem-
onstrated that ABCA1 mutation carriers show lower HDL-cholesterol
(HDL-C) levels and a larger atherosclerotic burden compared with con-
trols [52]. Unexpectedly, mice lacking ABCA1 and SR-BI display severe
hypocholesterolemia and foam cell accumulation, but have no athero-
sclerosis, which is mainly due to the absence of proatherogenic lipopro-
teins [53]. ABCA1 overexpression in the liver of LDLR−/− mice results in
accumulation of proatherogenic lipoproteins and enhanced atheroscle-
rosis [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 in-
gestion 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, en-
hances 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, unsat-
urated fatty acids suppress ABCA1 expression in RAW 264.7 macro-
phages by two distinct mechanisms: LXR-dependent transcriptional
repression possibly through modulating histone acetylation states,
and LXR-independent posttranslational inhibition [59]. Our previous
 X.-H. Yu et al. / Clinica Chimica Acta 424 (2013) 245–252
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.
studies indicate that IL-18 and IL-12 synergistically decrease ABCA1
levels in THP-1 macrophage-derived foam cells through the IL-18 re-
ceptor (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 cellu-
lar lipid accumulation within the intima [61]. Thus, miR-26 inhibitors
can be potentially used to treat atherosclerosis.
4.2. ABCG1
ABCG1 mediates cholesterol removal from macrophages to HDL
particles but not to lipid-free apoA-I. It has been shown that a func-
tional 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 athero-
sclerosis but causes retarded lesion progression in more advanced
stage of atherosclerosis in LDLR−/− mice, suggesting that the influ-
ence 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 ex-
pression 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 extra-
virgin olive oil (EVOO) for 12 weeks induces a concentration-
dependent upregulation of ABCG1 expression in human macrophages
249
[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 ex-
pression, indicating that gut microbiota is a potential novel target for pre-
vention 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].
4.3. SR-BI
SR-BI promotes cholesterol efflux from macrophages to HDL. A
genetic variant of the SR-BI in humans leads to a reduction in choles-
terol efflux from macrophages but has no significant increase in ath-
erosclerosis [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 macro-
phage 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 expres-
sion 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 in-
terference technique reduces atherosclerosis in rabbits fed with
cholesterol-rich diet, indicating that the effect of SR-BI on atherogen-
esis in rabbits is different from the one seen in rodents [75]. There-
fore, 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
250 X.-H. Yu et al. / Clinica Chimica Acta 424 (2013) 245–252
increases SR-BI expression and HDL-mediated cholesterol efflux from
macrophages via its plasma phenolic acids [78]. Hydrogen administra-
tion 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].
5. Conclusion and future directions
The balanced of cholesterol influx, esterification and release is nec-
essary to avoid lipid overload within macrophages, and ultimately,
atheroma development. Under atherogenic conditions, efflux of cho-
lesterol is decreased due to reduced expression of ABCA1, ABCG1
and SR-BI; however its uptake is increased due to enhanced expres-
sion of CD36 and SR-A as well as excess esterification of cholesterol oc-
curs 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 car-
diovascular diseases. K-604 and rimonabant, recently identified as po-
tent 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 reduc-
ing cholesterol uptake and/or promoting its removal. For instance,
seven phenolic acids, the major bioactive compounds in blueberries,
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.
have been recently reported to attenuate the formation of macro-
phage 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 atheroscle-
rotic 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 cardio-
vascular events [84]. Moreover, a large human genetics study shows
that genetic variants that enhance HDL-C levels do not necessarily as-
sociate 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 regu-
late 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.
Disclosure
The authors have declared no conflict of interest.
Acknowledgment
The authors gratefully acknowledge the financial support from
the National Natural Sciences Foundation of China (81070220 and
81170278), and Aid Program for Science and Technology Innovative
 X.-H. Yu et al. / Clinica Chimica Acta 424 (2013) 245–252
Research Team in Higher Educational Institutions of Human Province,
China (2008-244).
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