QJM Advance Access originally published online on October 28, 2005
QJM 2005 98(12):845-856; doi:10.1093/qjmed/hci136
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Review |
Reverse cholesterol transport and cholesterol efflux in atherosclerosis
From the Molecular Surgeon Research Center, Division of Vascular Surgery and Endovascular Therapy, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, USA
Address correspondence to Professor C. Chen, Michael E. DeBakey Department of Surgery, Baylor College of Medicine—NAB 2010, One Baylor Plaza, Houston, Texas 77030, USA. email: jchen{at}bcm.tmc.edu
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Summary |
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 Top Summary IntroductionOverview of RCT and...Clinical investigations on RCT...Animal models of RCT...In vitro studies on...ConclusionsReferences |
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Reverse cholesterol transport (RCT) is a pathway by which accumulated cholesterol is transported from the vessel wall to the liver for excretion, thus preventing atherosclerosis. Major constituents of RCT include acceptors such as high-density lipoprotein (HDL) and apolipoprotein A-I (apoA-I), and enzymes such as lecithin:cholesterol acyltransferase (LCAT), phospholipid transfer protein (PLTP), hepatic lipase (HL) and cholesterol ester transfer protein (CETP). A critical part of RCT is cholesterol efflux, in which accumulated cholesterol is removed from macrophages in the subintima of the vessel wall by ATP-binding membrane cassette transporter A1 (ABCA1) or by other mechanisms, including passive diffusion, scavenger receptor B1 (SR-B1), caveolins and sterol 27-hydroxylase, and collected by HDL and apoA-I. Esterified cholesterol in the HDL is then delivered to the liver for excretion. In patients with mutated ABCA1 genes, RCT and cholesterol efflux are impaired and atherosclerosis is increased. In studies with transgenic mice, disruption of ABCA1 genes can induce atherosclerosis. Levels of HDL are inversely correlated with incidences of cardiovascular disease. Supplementation with HDL or apoA-I can reverse atherosclerosis by accelerating RCT and cholesterol efflux. On the other hand, pro-inflammatory factors such as interferon-gamma (IFN-
), endotoxin, tumour necrosis factor-alpha (TNF-
) and interleukin-1 beta (IL-1ß), can be atherogenic by impairing RCT and cholesterol efflux, according to in vitro studies. RCT and cholesterol efflux play a major role in anti-atherogenesis, and modification of these processes may provide new therapeutic approaches to cardiovascular disease. Further research on new modifying factors for RCT and cholesterol efflux is warranted. |
Introduction |
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TopSummaryIntroductionOverview of RCT and...Clinical investigations on RCT...Animal models of RCT...In vitro studies on...ConclusionsReferences |
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Over the last few decades, our understanding of the basic mechanisms involved in atherosclerosis has progressed significantly. The important role of inflammation at all stages of the disease process is now recognized, including triggers, mediators and end-effectors. Many recent reviews have summarized these landmark events of atherogenesis.1–5 Plasma cholesterol levels are an important factor in atherosclerosis. Regulation of cholesterol levels is a complicated process, involving cholesterol uptake, biosynthesis, transport, metabolism, and secretion, and has been well described in several recent reviews.6–9 In this review, we focus mainly on cholesterol transport, and describe recent advances in the understanding of reverse cholesterol transport (RCT) and cholesterol efflux, processes which significantly affect atherogenesis.
RCT is a pathway that transports cholesterol from extrahepatic cells and tissues to the liver and intestine for excretion. By reducing accumulation of cholesterol in the wall of arteries, RCT may prevent development of atherosclerosis. Cholesterol efflux, part of the RCT process, is a major process by which macrophages within the vessel wall secrete cholesterol outside cells. Other important factors include high-density lipoprotein (HDL), a subfraction of human plasma lipoproteins with apolipoprotein A-I (apoA-I) as its principal apolipoprotein. HDL levels can determine the efficiency of RCT and cholesterol efflux.
First, we discuss how clinical studies have demonstrated the role of RCT and cholesterol efflux in cardiovascular disease. We then describe animal models and in vitro studies that shed light on the molecular mechanisms of RCT and cholesterol efflux in the vascular system. These animal and laboratory data may be useful for interpretation of clinical findings, and for future directions of clinical investigations.
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Overview of RCT and cholesterol efflux |
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TopSummaryIntroductionOverview of RCT and...Clinical investigations on RCT...Animal models of RCT...In vitro studies on...ConclusionsReferences |
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The sequence of events in RCT is described in Figure 1. ApoA-I is first produced mainly by the liver, and released into the plasma. Circulating apoA-I interacts with serum phospholipids and forms nascent discoidal HDL (ndHDL). Once ndHDL is generated, it triggers cholesterol efflux in the macrophages and fibroblasts in the subendothelial space. Externalized cholesterol is absorbed by ndHDL, and subsequently is esterified by lecithin:cholesterol acyltransferase (LCAT). HDL particles are enriched with cholesteryl ester and become larger, resulting in HDL3 and HDL2. Phospholipid transfer protein (PLTP) is involved in this process: for example, by fusing two HDL3 into one HDL2 molecule. If HDL molecules are enriched with triglyceride, they are processed by the enzyme hepatic lipase (HL) and become smaller and denser. HL can convert the phospholipid-rich HDL2 to HDL3. However, regulation of the balance of HL and PLTP is not clear. Cholesterol ester transfer protein (CETP) facilitates the equimolar exchange of cholesteryl esters from HDL for triglycerides in apoB100-containing lipoproteins. These cholesteryl esters are then delivered back to the liver via low-density-lipoprotein receptor (LDL-R), converted to bile salts, and eliminated through the gastrointestinal tract.
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As acceptors such as apoA-I and HDL approach macrophages in subintimal space, intracellular cholesterol can be released outside the cells for excretion, a process termed cholesterol efflux of macrophages (Figure 2). In this pathway, ATP-binding membrane cassette transport protein A1 (ABCA1) plays a major role in translocating cholesterol into the extracellular space.10 In addition to ABCA1, four other factors are known to be involved in the pathway. Scavenger receptor B1 (SR-B1) can induce cholesterol efflux by enabling HDL to bind to cells and reorganize lipids within cholesterol-rich domains in the plasma membrane.11,12 Caveolins are typically associated with caveolae, which are non-clatrin-coated plasma membrane microdomains rich in cholesterol and glycosphingolipids. Caveolins are small proteins (18–24 kDa) that have a hairpin loop conformation, with both the N and C termini exposed to the cytoplasm.13 These proteins have the capacity to bind cholesterol, and can transport cholesterol from the endoplasmic reticulum to the plasma membrane.14,15 A report showed that over-expression of caveolins enhances cholesterol efflux in hepatic cells without affecting ABCA1 expression, indicating the presence of a caveolin-dependent pathway.15 Sterol 27-hydroxylase (CYP27A1) is also known as a contributor to cholesterol efflux.17 CHOP cells transfected with CYP27A1 showed increased cholesterol efflux. Since ABCA-1 expression was not altered, CYP27A1 could cause cholesterol efflux independent of other factors. In addition to these pathways, cholesterol efflux can also occur via passive diffusion, in which cholesterol is desorbed down to the concentration gradient onto acceptor molecules.18 Thus, RCT and cholesterol efflux constitute an efficient pathway by which excess cholesterol can be removed out of the body. Although extensive studies have recently been performed, RCT is a complicated process and its regulation mechanisms are largely unknown. Several key factors described above are involved in the RCT and cholesterol efflux, but the inter-relationship among these factors is not clear.
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Clinical investigations on RCT and cholesterol efflux |
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TopSummaryIntroductionOverview of RCT and...Clinical investigations on RCT...Animal models of RCT...In vitro studies on...ConclusionsReferences |
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A variety of evidence shows that RCT and cholesterol efflux play a major role in preventing atherosclerosis in humans. In fact, congenital impairment in genes involved in cholesterol efflux may augment atherogenesis in some patients. On the other hand, acceleration of RCT and cholesterol efflux by increasing HDL or apoA-I levels may result in amelioration of atherosclerosis, suggesting a potential therapeutic tool for human atherosclerosis.
HDL levels and atherosclerosis
HDL has various species, identified on the basis of their major apolipoprotein (apo) components (apoA-I or apoA-II), density (HDL2 and HDL3) and electrophoretic mobility ( and pre-ß).19 Changes in HDL levels more closely reflect variations in the HDL2 subfraction rather than HDL3.20 Several studies have shown that low levels of HDL2 and HDL3 are associated with increased progression of atherosclerosis and risk of cardiovascular disease.21–25 Since HDL and ApoA-I are major receptors of cholesterol in the cholesterol efflux, increasing HDL levels may increase cholesterol efflux and RCT, contributing to reduced cardiovascular disease risks. Many attempts have been made to enhance HDL levels as anti-atherogenesis therapy.26,27
Statins are the inhibitors of hydroxymethyl glutaryl coenzyme A (HMG CoA) reductase, the rate-limiting enzyme in cholesterol biosynthesis. Statins could decrease intracellular hepatic cholesterol and up-regulate LDL receptors,28,29 which remove both LDL and triglyceride-rich lipoproteins (VLDL and IDL) from the circulation, thereby reducing plasma LDL and triglyceride levels. In addition, statins could also raise HDL levels,29,30 which may be mediated through increase in the synthesis and secretion of apoA-I.31 Clinical studies showed that atorvastatin increased apoA-I levels, and also decreased the CETP-mediated transfer of cholesterol from HDL, as a result of a reduction in apoB-containing lipoproteins (LDL, IDL, VLDL).32 Several intervention studies in both primary and secondary prevention support the benefit of treating patients who have low HDL levels with a statin to decrease cardiovascular risk in primary and secondary prevention settings.33,34
Fibric acid derivatives (fibrates) are agonists of peroxisome proliferator-activated receptor (PPAR)-, a nuclear hormone receptor involved in energy and lipid metabolism. Fibrates lower triglyceride levels very effectively, and raise HDL levels moderately.35 Fibrates are more effective in raising HDL levels when triglyceride levels are elevated. Gemfibrozil therapy significantly reduced cardiovascular disease, with a modest increase in HDL levels.36 A recent VA-HIT study demonstrated the benefit of gemfibrozil therapy in patients with low HDL and LDL levels.37,38
Nicotinic acid, or niacin, is the most effective agent for raising HDL levels, resulting in increases of up to 35%. Niacin also lowers triglyceride levels, reduces LDL levels, and modestly lowers lipoprotein (a) levels.35,39,40 Several clinical trials have found niacin to be effective, alone or in combination with other drugs, in preventing coronary events, slowing atherosclerotic disease progression, and promoting lesion regression.41
Clinical studies demonstrated that oestrogen replacement therapy in post-menopausal women increased apoA-I concentrations by suppressing the activity of hepatic triglyceride lipase (HTGL) and SR-BI.42 More recent clinical studies showed that oral administration of oestrogen could elevate HDL and inflammation proteins such as C-reactive protein (CRP) and serum amyloid (SAA), which may incorporate into HDL particles.43,44 SAA incorporation in HDL may inhibit its ability to deliver free cholesterol to the liver for clearance, thereby contributing to higher levels of HDL cholesterol, and also reduce its antioxidant properties.45 These observations may explain the limitations of the cardiovascular benefits of oestrogen replacement therapy, even though HDL levels are increased in these patients.
ApoA-I promotes cholesterol efflux and RCT, transferring cholesterol from peripheral cells to the liver for subsequent elimination. Eriksson et al. infused human proapoA-I (precursor of apo A-I) liposome complexes into patients with familial hypercholesterolemia, and measured the faecal excretion of bile acids and neutral sterols.46 The faecal excretion of cholesterol increased in all subjects, corresponding to the removal of excess cholesterol after infusion. This result implies that infusion of proapoA-I liposomes in humans promotes net cholesterol excretion from the body, providing a mechanism that may be useful in the treatment of atherosclerosis.
ApoA-IMilano is a variant of apoA-I identified in individuals in rural Italy who exhibit very low levels of HDL.47 ApoA-IMilano appears to be atheroprotective by promoting cellular cholesterol efflux.48 In a recent study, infusion of apoA-IMilano reduced the atheroma size in the patients with coronary disease by 4.2%, compared with controls.49 The above reports provide support for the concept that elevating HDL decreases cardiovascular diseases. HDL therapies using infusion of apoA-I or apoA-IMilano might have the potential to be therapeutic tools for the disease.
Gene activities or mutations in RCT and cholesterol efflux
ABCA1 is an integral membrane protein that utilizes ATP as a source of energy for transporting lipids and other metabolites across membranes, where they are removed from cells by apolipoproteins such as apoA-I.50 Tangier disease (TD) is an autosomal recessive disorder of lipid metabolism associated with cardiovascular disease.51 It is also characterized by the absence of plasma HDL, and deposition of cholesteryl esters in the reticulo-endothelial system, with splenomegaly and enlargement of tonsils and lymph nodes. In TD fibroblasts, HDL-mediated cholesterol efflux and intracellular lipid trafficking and turnover are abnormal, and mutations in ABCA1 are believed to be responsible.52,53 Abnormalities in ABCA-1 can also induce low levels of HDL. Clee et al. investigated the phenotypes of individuals with TD and familial hypoalphalipoproteinaemia.54 They found that patients with mutations in the ABCA1 gene have low levels of HDL and high levels of triglycerides. These data provide direct evidence that impairment of cholesterol efflux and RCT is associated with reduced plasma HDL levels and subsequent cardiovascular disease.
CETP is physically associated with HDL particles and facilitates the transport of cholesteryl ester from HDL to apoB-containing lipoproteins. A decrease of CETP activity may increase HDL-C and decrease VLDL-C and LDL-C. Thus, CETP simultaneously affects the composition and concentration of apoA–/– and apoB-containing lipoproteins. Clinical studies demonstrate a low prevalence of coronary heart disease among subjects with CETP deficiency.55 Genetic polymorphisms causing CETP deficiency are particularly observed in Asian populations.56 Although CETP deficiency might prevent atherogenesis by increasing HDL-cholesterol levels,57 their effect has been controversial. Studies performed in Japan indicate that CETP deficiency might increase cardiovascular disease risks.58 In spite of the confusion about the role of CETP, the use of CETP inhibition in humans has attracted attention as a new strategy. The compound JTT-705, a direct inhibitor of CETP, raises HDL in a dose-dependent fashion.59 However, it remains uncertain whether the observed increase in HDL leads to a reduction in coronary artery disease. Davidson et al. reported on a CETP vaccine that induces auto-antibodies that specifically bind and inhibit endogenous CETP, with the intention of increasing HDL and reducing the development of atherosclerosis.60 They demonstrated that 53% of patients developed the auto-antibodies after two injections of the vaccine. Future research will determine the right dose of the vaccine and its effect on HDL levels.
LCAT is a key enzyme necessary for extracellular cholesterol metabolism.61–63 LCAT may facilitate the uptake of cholesterol from peripheral tissues into HDL particles by maintaining a concentration gradient for the efflux of free cholesterol,64 and may play a major role in RCT. Therefore, if LCAT is impaired, mature HDL generation would presumably be decreased, resulting in augmentation of atherosclerosis. LCAT deficiency syndromes have been reported in humans. Fish-eye disease (FED) is a disorder with a selective defect in HDL- or -associated LCAT activity, presenting with pronounced corneal opacification and a marked reduction in HDL cholesterol.65–67 However, cardiovascular risk does not seem to be increased in FED, for unknown reasons.68 Various animal studies have attempted to clarify this discrepancy, but the precise mechanism still remains controversial.
Hepatic lipase (HL) plays a major role in lipoprotein metabolism as a lipolytic enzyme that hydrolyses triglycerides and phospholipids in chylomicron remnants, intermediate density lipoprotein (IDL), and HDL. HL can convert the phospholipid-rich HDL2 to HDL3. Patients with HL deficiency present with hypercholesterolaemia or hypertriglyceridaemia and accumulate ß-VLDLs, chylomicron remnants, IDLs, triglyceride-rich LDLs, and HDLs.69–71
PLTP facilitates the in vivo transfer of phospholipids from triglyceride-rich lipoproteins to HDL during lipolysis by lipoprotein lipase. These phospholipids are present in surface fragments released from chylomicrons and VLDL during lipolysis, and are important precursors of plasma HDL. The interaction of PLTP with typical HDL results in the release of small, lipid-poor pre-ß-HDL particles, and at the same time produces large -HDL (HDL2-like particles) by a process that involves particle fusion.72,73 Plasma PLTP activity was elevated in patients with insulin-resistant diabetes and obesity, and it was also correlated with high plasma triglycerides and low HDL-cholesterol.74–76 Elevated PLTP activities in these patients may result from elevated rates of VLDL turnover, and inhibition of VLDL synthesis. The regulation of HL and PLTP levels, and their impact on atherosclerosis, is unclear. Since functions of HL and PLTP may regulate both proatherogenic and antiatherogenic factors, the net effect of these protein-induced alterations in plasma lipoproteins on atherosclerosis is not easily predictable. Further investigations are warranted.
Life-style modification and RCT and cholesterol efflux
Various life-style factors affect the progression of atherogenesis, and recent reports suggest that modulation of RCT and cholesterol efflux can play a major role in that process. Beulens et al. suggest that moderate alcohol intake may reduce cardiovascular risk by increasing RCT and cholesterol efflux.77 They found that ABCA1-dependent cholesterol efflux in macrophages were increased in humans consuming alcohol (vs. water). Higher levels of HDL-C and apoA-I were also seen in the alcohol group. In another report, HDL-C levels were increased in athletes, suggesting that regular exercise might have a protective effect on atherogenesis by stimulating RCT and cholesterol efflux.78 By contrast, smoking can impair remodelling of HDL-C by inhibiting many steps in RCT and cholesterol efflux, increasing risks for cardiovascular disease.79
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Animal models of RCT and cholesterol efflux |
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TopSummaryIntroductionOverview of RCT and...Clinical investigations on RCT...Animal models of RCT...In vitro studies on...ConclusionsReferences |
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In support of the human studies, a number of experiments using transgenic animals indicate that disruption of one or more steps in RCT and cholesterol efflux can result in accelerated atherosclerosis, whereas over-expression of pivotal proteins in RCT and cholesterol efflux, such as apoA-I, PLTP, LCAT, and SR-B1, exerts atheroprotective effects.80 For instance, increased accumulation of cholesterol in peripheral tissues is observed in animals with apoA-I or ABCA1 deficiency, while over-expression of those genes may reduce atherogenesis.
ABCA1, which facilitates cellular cholesterol efflux, has generated considerable interest as a potential anti-atherogenic agent. In transgenic mice that over-express ABCA1, increased ABCA1 raised plasma HDL levels, increased cholesterol efflux from macrophages, and reduced diet-induced atherosclerosis in different mouse models.81 For example, transgenic mice strongly expressing ABCA1 showed an anti-atherogenic lipid profile, with elevated levels of HDL-C and apoA-I, and significantly less aortic atherosclerosis.82,83 In a recent study, increased recruitment of ABCA1-deficient leukocytes (monocytes/macrophages) was seen in the arterial wall of LDL-receptor deficient (LDLr–/–) mice.84 This indicates that leukocyte ABCA1 plays a critical role in the protection against atherosclerosis, and that ABCA1 is a leukocyte factor that controls the recruitment of inflammatory cells.
In ABCA1–/– mouse models, lack of HDL and apoA-I is accompanied by accumulation of lipid-laden macrophages in the lungs.85 Aiello et al. examined whether the complete absence of ABCA1 or selected inactivation in macrophages was accompanied by an increase in atherosclerotic lesion progression in hypercholesterolaemic apolipoprotein-E-deficient (apoE–/–) mice and LDLR–/– mice.86 Interestingly, the absence of ABCA1 led to reduced plasma cholesterol levels in both groups, but the complete absence of ABCA1 did not affect the development of atherosclerotic lesions in either the LDLr–/– or the apoE–/– mice. In contrast, bone marrow transplantation studies demonstrated that the selective inactivation of ABCA1 in macrophages markedly increased atherosclerosis and foam cell accumulation in apoE–/–. It is possible that the complete absence of ABCA1 induced another compensating anti-atherogenic effect. ABCA1 deficiency in macrophages, however, demonstrates the anti-atherogenic properties of ABCA1, independent of plasma lipids and HDL levels. Groen et al.87 studied the effect of ABCA1 on hepatobiliary cholesterol transport in ABCA1 knockout mice. ABCA1 knockout significantly blocked cellular cholesterol efflux to apoA-I, thereby reducing HDL formation (almost completely lacking HDL) in these mice. These data indicate that ABCA1 is critical to cholesterol efflux to HDL. However, there were unexpected data indicating that hepatobiliary cholesterol transport was not changed in ABCA1 knockout mice with very low HDL levels, as compared to wild-type mice. It is possible that compensation may occur in these ABCA1 knockout mice, including increased hepatic cholesterol synthesis or increased VLDL/LDL.88 Thus, this study generates some uncertainties about the role of HDL in RCT in mice. Further studies are required to clarify the underlying mechanisms.
Although CETP is a critical factor in RCT, with the ability to transport cholesteryl ester from HDL, several species, including mice and rats, are naturally deficient in CETP. In transgenic mice with the human CETP gene, HDL levels were decreased, while VLDL and LDL cholesterol and apoB levels were increased.89,90 In both apoE-knockout mice and LDL-receptor-knockout mice, introduction of the human CETP gene with an atherogenic diet resulted in the formation of spontaneous atherosclerosis.91 Introduction of a simian CETP gene into mice also resulted in advanced atherosclerotic lesion formation, which may be due to a redistribution of cholesterol from HDLs to the VLDL/LDL fraction.92 These studies support the hypothesis that CETP is pro-atherogenic. However, several other studies in mice do not support this hypothesis. Over-expression of human CETP genes in mice, with over-expression of human apoC-III, showed an anti-atherogenic effect.93 This effect was also observed in a hypertriglyceridaemic mouse model produced by streptozotocin-induced diabetes and lipoprotein lipase deficiency.94 The mechanisms underlying these ambiguities are not clear.
Intravenous infusion of apoA-I and transgenic expression of human apoA-I in animal models are both anti-atherogenic, and can stimulate atheromatous plaque resorption.95,96 Recently, an edible form of apoA-I mimetic peptides composed of D-amino acids (D-4F) was developed, and administration of the peptide decreased atheromatous lesions by 79% in LDLR–/– mice fed a Western diet.97 The authors further demonstrated that D-4F can cause formation of pre-ß HDL, which induced increased cholesterol efflux in macrophages in apoE–/– mice.98 The introduction of recombinant apoA-IMilano into apoE-deficient mice and rabbits reduced the lipid content of atheromatous plaques.99,100 It is likely that the use of apoA-I or mimicking peptides has potential therapeutic applications in patients with atherosclerosis.
In addition to its functions in mediating the transfer of phospholipid between lipoproteins and catalysing HDL conversion reactions, PLTP appears to interact with ABCA1, and mediate the net transfer of lipid from cells to apoA-I and ndHDL particles.101 PLTP may therefore participate in RCT and cholesterol efflux by regenerating ndHDL during HDL conversion, and facilitating the lipidation of ndHDL in the subendothelial space. Despite these observations, when transgenic mice over-expressing human PLTP were fed a high-cholesterol diet, serum HDL decreased, and aortic atherosclerosis increased significantly.102
The roles of LCAT in RCT and cholesterol efflux still remain unclear, given that patients with LCAT deficiency do not have significantly increased cardiovascular disease.68 Various animal studies have attempted to elucidate the mechanisms, but have not provided clear answers. For example, transgenic rabbits over-expressing LCAT have shown increased HDL levels and reduced atherosclerosis,103 whereas mice with enhanced LCAT expression have increased atherosclerosis, despite high HDL levels.104 Oxidative stress is elevated in LCAT–/– mice with enhanced vascular ring superoxide production. Ng et al. cross-bred LCAT–/– mice with apoE–/– mice, and found that LCAT–/–xapoE–/– mice had decreased atherosclerosis compared to LCAT+/+xapoE–/– mice.105 It may be possible that increased oxidative stress was reversed in a hyperlipidaemic background, due to redistribution of paraoxonase, resulting in ameliorated atherogenesis. The above reports suggest that other factors such as modification of oxidative stress may be involved in effects of LCAT.
Rodents under oestrogen therapy have greater concentrations of apoA-I mRNA levels. It is believed that the increase in apoA-I expression by estrogens is modulated by the oestrogen receptor via an indirect effect of the hormone, and in HepG2 cells, estradiol potentiated the synergistic interactions between two transcription factors (hepatic nuclear factors 3a and 4, HNF-3a/HNF-4)106 that bind to the apoA-I promoter, and is believed to up-regulate apoA-I promoter activity.107
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In vitro studies on modification of RCT and cholesterol efflux |
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TopSummaryIntroductionOverview of RCT and...Clinical investigations on RCT...Animal models of RCT...In vitro studies on...ConclusionsReferences |
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There should be many factors that modify RCT and cholesterol efflux. For example, some pro-inflammatory factors can impair RCT and cholesterol efflux, whereas others may accelerate the pathway in cell culture models. Understanding and exploration of these factors may reveal underlying mechanisms of RCT and cholesterol efflux, and subsequently provide new therapeutic approaches.
Activated CD4+ T cells present in the atherosclerotic lesion can secrete interferon-gamma (IFN-).108 The incubation of foam cells with IFN- results in the reduction of HDL3-mediated cholesterol efflux.109 This decrease is not observed in other macrophage-activating factors, such as colony-stimulating factor. These findings suggest that IFN- contributes to the progression of an atherosclerotic lesion by altering the pathway of intracellular cholesterol trafficking in macrophage foam cells. Reiss et al. suggest that anti-inflammatory adenosine A2A receptor (A2AR) can minimize atherosclerotic changes.110 They showed that a selective A2AR agonist, CGS-21680, inhibits foam cell formation in human macrophages stimulated with immune-complex and IFN-. This implies a possible novel approach to developing agents that prevent atherosclerosis.
In addition to ABCA1, ATP-binding membrane cassette transporter G1 (ABCG1) is also known to mediate cholesterol removal from macrophages to HDL. When endotoxin or cytokines such as tumour necrosis factor-alpha (TNF-) and interleukin-1 beta (IL-1ß) were incubated with macrophages, the mRNA levels of ABCA1 and ABCG1 are decreased.111 The effect is rapid and sustained, and is associated with a reduction in ABCA1 protein levels. These reports support the idea that reduction in ABCA1 and ABCG1 in macrophages during the host response to infection and inflammation may aggravate atherosclerosis.
Elevated levels of triacylglycerol-rich lipoprotein (TGRL), including chylomicron remnants, VLDL, and IDL, are risk factors for coronary artery disease.112 Undegraded TGRL and their remnants are present within human and experimental atherosclerotic lesions.113 A recent study showed that TGRL can inhibit the efflux of cholesterol from macrophages to apoA-I.114 This inhibitory effect of TGRL is seen only in cholesterol-loaded foamy macrophages, and not in naive cells. During extended efflux periods, TGRL effectively blocks the ability of apoA-I to reduce macrophage cholesterol mass. The inhibitory mechanism is unclear, but it seems possible that pre-incubation with TGRL might affect the expression of one of the proteins (ABCA1, SR-B1 and apoE) involved in movement of cholesterol to the cell surface, and affect the intracellular pools of free cholesterol and stored cholesteryl ester available within the cells.
In contrast to the above reports, transforming growth factor-beta (TGF-ß) is known to have anti-inflammatory properties, as evidenced by the profound systemic inflammatory response reported for TGF-ß–/– mice.115 In atherosclerosis, TGF-ß could contribute to plaque stability through the inhibition of metalloproteinase activity and increase in matrix deposition.116 TGF-ß-treated macrophages exhibited a significant increase in cholesterol efflux mediated by apoA-I or HDL.117 The increase in apoA-I-mediated efflux is consistent with an increase at both the transcriptional and translational levels in the amount of ABCA1 expression in TGF-ß-treated foam cells. TGF-ß reverses the IFN- mediated inhibition of cholesterol efflux in macrophage-derived foam cells by mitigating the inhibitory effects of IFN- on ABCA1 expression. These findings support the notion that TGF-ß may have atheroprotective properties by increasing efflux and reducing macrophage foam cell formation.
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Conclusions |
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TopSummaryIntroductionOverview of RCT and...Clinical investigations on RCT...Animal models of RCT...In vitro studies on...ConclusionsReferences |
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Numerous studies in humans, animals, and in vitro, are addressing the importance of RCT and cholesterol efflux in atherogenesis. It is very possible that augmentation of RCT and cholesterol efflux could be therapeutically useful. Potential major strategies include accelerating RCT and cholesterol efflux, which can be activated by increasing HDL and apoA-I levels, or by stimulating PLTP or CETP. Cholesterol efflux can be enhanced by facilitating pathways including ABCA1, SR-B1, caveolin and Cyp27A1. Blocking inflammatory factors should also be useful. However, uncertainties remain about the impact of RCT and cholesterol efflux on cardiovascular disease. Further exploration of modifiers of RCT and cholesterol efflux is warranted. Gaining insight into the whole picture of RCT and cholesterol efflux may enable us to develop more effective therapies for atherosclerosis in the future.
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Acknowledgments |
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This work was supported by National Institutes of Health Grants R01HL61943, R01HL65916, R01HL60135 and R01HL72716 (C. Chen); and R01DE015543 (Q. Yao).
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References |
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TopSummaryIntroductionOverview of RCT and...Clinical investigations on RCT...Animal models of RCT...In vitro studies on...ConclusionsReferences |
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1. Ross R. Atherosclerosis—an inflammatory disease. N Engl J Med 1999; 340:115–26.
2. Libby P. Inflammation in atherosclerosis. Nature 2002; 420:868–74.[CrossRef][Medline]
3. Hansson GK. Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med 2005; 352:1685–95.
4. Lusis AJ, Fogelman AM, Fonarow GC. Genetic basis of atherosclerosis: part I: new genes and pathways. Circulation 2004; 110:1868–73.
5. Lusis AJ, Fogelman AM, Fonarow GC. Genetic basis of atherosclerosis: part II: clinical implications. Circulation 2004; 110:2066–71,
6. Ory DS. Nuclear receptor signaling in the control of cholesterol homeostasis: have the orphans found a home? Circ Res 2004; 95:660–70.
7. Payne AH, Hales DB. Overview of steroidogenic enzymes in the pathway from cholesterol to active steroid hormones. Endocrine Rev 2004; 25:947–70.
8. von Bergmann K, Sudhop T, Lutjohann D. Cholesterol and plant sterol absorption: recent insights. Am J Cardiol 2005; 96:10–14D.[CrossRef]
9. Martin S, Parton RG. Caveolin, cholesterol, and lipid bodies. Sem Cell Dev Biol 2005; 16:163–74.[CrossRef][ISI][Medline]
10. Oram JF, Vaughan AM. ABCA1-mediated transport of cellular cholesterol and phospholipids to HDL apolipoproteins. Curr Opin Lipidol 2000; 11:253–60.[CrossRef][ISI][Medline]
11. Williams DL, Connelly MA, Temel RE, Swarnakar S, Phillips MC, de la Llera-Moya M, Rothblat GH. Scavenger receptor BI and cholesterol trafficking. Curr Opin Lipidol 1999; 10:329–39.[CrossRef][ISI][Medline]
12. de la Llera-Moya M, Rothblat GH, Connelly MA, Kellner-Weibel G, Sakr SW, Phillips MC, Williams DL. Scavenger receptor BI (SR-BI) mediates free cholesterol flux independently of HDL tethering to the cell surface. J Lipid Res 1999; 40:575–80.
13. Krajewska WM, Maslowska I. Caveolins: structure and function in signal transduction. Cell Mol Biol Lett 2004; 9:195–220.[ISI][Medline]
14. Murata M, Peranen J, Schreiner R, Wieland F, Kurzchalia TV, Simons K. VIP21/caveolin is a cholesterol-binding protein. Proc Natl Acad Sci USA 1995; 92:10339–43.
15. Smart EJ, Ying Y, Donzell WC, Anderson RG. A role for caveolin in transport of cholesterol from endoplasmic reticulum to plasma membrane. J Biol Chem 1996; 271:29427–35.
16. Fu Y, Hoang A, Escher G, Parton RG, Krozowski Z, Sviridov D. Expression of caveolin-1 enhances cholesterol efflux in hepatic cells. J Biol Chem 2004; 279:14140–6.
17. Escher G, Krozowski Z, Croft KD, Sviridov D. Expression of sterol 27-hydroxylase (CYP27A1) enhances cholesterol efflux. J Biol Chem 2003; 278:11015–19.
18. Kawano M, Miida T, Fielding CJ, Fielding PE. Quantitation of pre beta-HDL-dependent and nonspecific components of the total efflux of cellular cholesterol and phospholipid. Biochemistry 1993; 32:5025–8.[CrossRef][Medline]
19. Shah PK. Focus on HDL: A new treatment paradigm for athero-thrombotic vascular disease. Exp Opin Invest Drugs 2000; 9:2139–46.[CrossRef]
20. Bakogianni MC, Kalofoutis CA, Skenderi KI, Kalofoutis AT. Clinical evaluation of plasma high-density lipoprotein subfractions (HDL2, HDL3) in non-insulin-dependent diabetics with coronary artery disease. J Diabetes Complications 2001; 15:265–9.[Medline]
21. Miller NE, Hammett F, Saltissi S, et al. Relation of angiographically defined coronary artery disease to plasma lipoprotein subfractions and apolipoproteins. BMJ 1981; 282:1741–4.[ISI][Medline]
22. Salonen JT, Salonen R, Seppanen K, Rauramaa R, Tuomilehto J. HDL, HDL2, and HDL3 subfractions, and the risk of acute myocardial infarction. A prospective population study in eastern finnish men. Circulation 1991; 84:129–39.
23. Johansson J, Carlson LA, Landou C, Hamsten A. High density lipoproteins and coronary atherosclerosis. A strong inverse relation with the largest particles is confined to normotriglyceridemic patients. Arterioscler Thromb 1991; 11:174–82.
24. Sweetnam PM, Bolton CH, Yarnell JW, et al. Association of the HDL2 HDL3 cholesterol subfractions with the development of ischemic heart disease in British men. The caerphilly and speedwell collaborative heart disease studies. Circulation 1994; 90:769–74.
25. Ruotolo G, Ericsson CG, Tettamanti C, et al. Treatment effects on serum lipoprotein lipids, apolipoproteins and low density lipoprotein particle size and relationships of lipoprotein variables to progression of coronary artery disease in the Bezafibrate Coronary Atherosclerosis Intervention Trial (BECAIT). J Am Coll Cardiol 1998; 32:1348–656.
26. Gordon DJ, Probstfield JL, Garrison RJ, Neaton JD, Castelli WP, Knoke JD, Jacobs DR, Jr., Bangdiwala S, Tyroler HA. High-density lipoprotein cholesterol and cardiovascular disease. Four prospective American studies. Circulation 1989; 79:8–15.
27. Castelli WP, Anderson K, Wilson PW, Levy D. Lipids and risk of coronary heart disease. The Framingham Study. Ann Epidemiol 1992; 2:23–8.[Medline]
28. Vega G-L, Grundy SM. Effect of statins on metabolism of apo-B-containing lipoproteins in hypertriglyceridemic men. Am J Cardiol 1998; 81:36–42B.[CrossRef][ISI][Medline]
29. Knopp RH. Drug treatment of lipid disorders. N Engl J Med 1999; 341:498–511.
30. Maron DJ, Fazio S, Linton MF. Current perspectives on statins. Circulation 2000; 101:207–13.
31. Bonn V, Cheung RC, Chen B, Taghibiglou C, Van Iderstine SC, Adlei K. Simvastatin, an HMG-CoA reductase inhibitor, induces the synthesis and secretion of apolipoprotein AI cells in HepG2 cells and primary hamster hepatocytes. Atherosclerosis 2002; 163:59–68.[Medline]
32. Guerin M, Egger P, Soudant C, et al. Dose-dependent action of atorvastatin in type IIB hyperlipidemia: Preferential and progressive reduction of atherogenic apoB-containing lipoprotein subclasses (VLDL-2, IDL, small dense LDL) and stimulation of cellular cholesterol efflux. Atherosclerosis 2002; 163:287–96.[CrossRef][ISI][Medline]
33. Downs JR, Clearfield M, Weis S, et al. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. JAMA 1998; 279:1615–22.
34. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20536 high-risk individuals: a randomised placebo-controlled trial. Lancet 2002; 360:7–22.[CrossRef][ISI][Medline]
35. Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults. Executive Summary of the third report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III). JAMA 2001; 285:2486–97.
36. Frick MH, Elo O, Haapa K, et al. Helsinki Heart Study: primary-prevention trial with gemfibrozil in middle-aged men with dyslipidemia. Safety of treatment, changes in risk factors, and incidence of coronary heart disease. N Engl J Med 1987; 317:1237–45.[Abstract]
37. Rubins HB, Robins SJ, Collins D, et al. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. N Engl J Med 1999; 341:410–18.
38. Robins SJ, Collins D, Wittes JT, et al. Relation of gemfibrozil treatment and lipid levels with major coronary events: VA-HIT: a randomized controlled trial. JAMA 2001; 285:1585–91.
39. Guyton JR, Blazing MA, Hagar J, et al. Extended-release niacin vs gemfibrozil for the treatment of low levels of high-density lipoprotein cholesterol: Niaspan-Gemfibrozil Study Group. Arch Intern Med 2000; 160:1177–84.
40. Canner PL, Berge KG, Wenger NK, et al. Fifteen year mortality in Coronary Drug Project patients: long-term benefit with niacin. J Am Coll Cardiol 1986; 8:1245–55.[Abstract]
41. Brown BG, Zhao X-Q, Chait A, et al. Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease. N Engl J Med 2001; 345:1583–92.
42. von Eckardstein A, Nofer JR, Assmann G. High density lipoproteins and arteriosclerosis. Role of cholesterol efflux and reverse cholesterol transport. Arterioscler Thromb Vasc Biol 2001; 21:13–27
43. Abbas A, Fadel P, Wang Z, Arbique D, Jialal I, Vongpatanasin W. Contrasting effects of oral versus transdermal estrogen on serum amyloid A (SAA) and high-density lipoprotein–SAA in postmenopausal women. Arterioscler Thromb Vasc Biol 2004; 24:e164–7.
44. Cushman M, Legault C, Barrett-Connor E, Stefanick ML, Kessler C, Judd HL, Sakkinen PA, Tracy RP. Effect of postmenopausal hormones on inflammation-sensitive proteins. The Postmenopausal Estrogen/Progestin Interventions (PEPI) study. Circulation 1999; 100:717–22.
45. Navab M, Berliner JA, Subbanagounder G, Hama S, Lusis AJ, Castellani LW, Reddy S, Shih D, Shi W, Watson AD, Van Lenten BJ, Vora D, Fogelman AM. HDL and the inflammatory response induced by LDL-derived oxidized phospholipids. Arterioscler Thromb Vasc Biol 2001; 21:481–8.
46. Eriksson M, Carlson LA, Miettinen TA, Angelin B. Stimulation of fecal steroid excretion after infusion of recombinant proapolipoprotein A-I. Potential reverse cholesterol transport in humans. Circulation 1999; 100:594–8.
47. Weisgraber KH, Rall SC, Jr., Bersot TP, Mahley RW, Franceschini G, Sirtori CR. Apolipoprotein A-IMilano. Detection of normal A-I in affected subjects and evidence for a cysteine for arginine substitution in the variant A-I. J Biol Chem 1983; 258:2508–13.
48. Chiesa G, Sirtori CR. Apolipoprotein A-IMilano: current perspectives. Curr Opin Lipidol 2003; 14:159–63.[CrossRef][Medline]
49. Nissen SE, Tsunoda T, Tuzcu EM, Schoenhagen P, Cooper CJ, Yasin M, Eaton GM, Lauer MA, Sheldon WS, Grines CL, Halpern S, Crowe T, Blankenship JC, Kerensky R. Effect of recombinant ApoA-I Milano on coronary atherosclerosis in patients with acute coronary syndromes: a randomized controlled trial. JAMA 2003; 290:2292–300.
50. Dean M, Yannick H, Allikmet R, Chimini G. ABC transporters: from genes to diseases. J Lipid Res 2001; 42:1007–17.
51. Serfaty-Lacrosniere C, Civeira F, Lanzberg A, Isaia P, Berg J, Janus ED, Smith MP, Jr., Pritchard PH, Frohlich J, Lees RS. Homozygous Tangier disease and cardiovascular disease. Atherosclerosis 1994; 107:85–98.[CrossRef][ISI][Medline]
52. Bodzioch M, Orso E, Klucken J, et al. The gene encoding ATP-binding cassette transporter 1 is mutated in Tangier disease. Nat Genet 1999; 22:347–51.[CrossRef][ISI][Medline]
53. Brooks-Wilson A, Marcil M, Clee SM, et al. Mutations in ABC1 in Tangier disease and familial high-density lipoprotein deficiency. Nat Genet 1999; 22:336–45.[CrossRef][ISI][Medline]
54. Clee SM, Kastelein JJ, van Dam M, et al. Age and residual cholesterol efflux affect HDL cholesterol levels and coronary artery disease in ABCA1 heterozygotes. J Clin Invest 2000; 106:1263–70.[ISI][Medline]
55. Moriyama Y, Okamura T, Inazu A, Doi M, Iso H, Mouri Y, Ishikawa Y, Suzuki H, Iida M, Koizumi J, Mabuchi H, Komachi Y. A low prevalence of coronary heart disease among subjects with increased high-density lipoprotein cholesterol levels, including those with plasma cholesteryl ester transfer protein deficiency. Prev Med 1998; 27:659–67.[CrossRef][ISI][Medline]
56. Wu JH, Lee YT, Hsu HC, Hsieh LL. Influence of CETP gene variation on plasma lipid levels and coronary heart disease: a survey in Taiwan. Atherosclerosis 2001; 159:451–8.[CrossRef][ISI][Medline]
57. Inazu A, Jiang XC, Haraki T, Yagi K, Kamon N, Koizumi J, Mabuchi H, Takeda R, Takata K, Moriyama Y. Genetic cholesteryl ester transfer protein deficiency caused by two prevalent mutations as a major determinant of increased levels of high density lipoprotein cholesterol. J Clin Invest 1994; 94:1872–82.[ISI][Medline]
58. Hirano K, Yamashita S, Nakajima N, Arai T, Maruyama T, Yoshida Y, Ishigami M, Sakai N, Kameda-Takemura K, Matsuzawa Y. Genetic cholesteryl ester transfer protein deficiency is extremely frequent in the Omagari area of Japan. Marked hyperalphalipoproteinemia caused by CETP gene mutation is not associated with longevity. Arterioscler Thromb Vasc Biol 1997; 17:1053–9.
59. de Grooth GJ, Kuivenhoven JA, Stalenhoef AF, de Graaf J, Zwinderman AH, Posma JL, van Tol A, Kastelein JJ. Efficacy and safety of a novel cholesteryl ester transfer protein inhibitor, JTT-705, in humans: a randomized phase II dose-response study. Circulation 2002; 105:2159–65.
60. Davidson MH, Maki K, Umporowicz D, Wheeler A, Rittershaus C, Ryan U. The safety and immunogenicity of a CETP vaccine in healthy adults. Atherosclerosis 2003; 169:113–20.[CrossRef][Medline]
61. Norum, KR, Gjone E, Glomset JA. Familial lecithin:cholesterol acyltransferase deficiency, including fish eye disease. In: Scriver MCR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic Basis of Inherited Disease. New York, McGraw-Hill, 1989:1181–94.
62. Fielding CJ. Lecithin:cholesterol acyltransferase. In: Esfahani M, Swaney JB, eds. Advances in Cholesterol Research. Caldwell, The Telford Press, 1990:271–314.
63. Jonas A. Lecithin-cholesterol acyltransferase in the metabolism of high-density lipoproteins. Biochim Biophys Acta 1991; 1084:205–20.[Medline]
64. Fielding CJ. Increased free cholesterol in plasma low and very low density lipoproteins. J Lipid Res 1984; 25:1624–8.[Medline]
65. Carlson LA, Philipson B. Fish-eye disease: a new familial condition with massive corneal opacities and dyslipoproteinemia. Lancet 1979; 2:921–3.
66. Carlson LA. Fish eye disease: a new familial condition with massive corneal opacities and dyslipoproteinemia. Eur J Clin Invest 1982; 12:41–53.[Medline]
67. Carlson LA, Holmquist L. Evidence for deficiency of high density lipoprotein lecithin:cholesterol acyltransferase activity (alpha-LCAT) in fish eye disease. Acta Med Scand 1985; 218:189–96.[Medline]
68. Kuivenhoven JA, Pritchard H, Hill J, Frohlich J, Assmann G, Kastelein J. The molecular pathology of lecithin:cholesterol acyltransferase (LCAT) deficiency syndromes. J Lipid Res 1997; 38:191–205.[Abstract]
69. Jansen H, Verhoeven AJ, Weeks L, Kastelein JJ, Halley DJ, van den Ouweland A, Jukema JW, Seidell JC, Birkenhaer JC. Common C-to-T substitution at position –480 of the hepatic lipase promoter associated with a lowered lipase activity in coronary artery disease patients. Arterioscler Thromb Vasc Biol 1997; 17:2837–42.
70. Breckenridge WC, Little JA, Alaupovic P, Wang CS, Kuksis A, Kakis G, Lindgren F, Gardiner G. Lipoprotein abnormalities associated with a familial deficiency of hepatic lipase. Atherosclerosis 1982; 45:161–79.[CrossRef][ISI][Medline]
71. Hegele RA, Little JA, Vezina C, Maguire GF, Tu L, Wolever TS, Jenkins DJA, Connelly PW. Hepatic lipase deficiency: Clinical, biochemical, and molecular genetic characteristics. Arterioscler Thromb 1993; 13:720–8.
72. Rye K-A, Clay MA, Barter PJ. Remodelling of high density lipoproteins by plasma factors. Atherosclerosis 1999; 145:227–38.[CrossRef][ISI][Medline]
73. Huuskonen J, Olkkonen VM, Jauhiainen M, Ehnholm C. The impact of phospholipid transfer protein (PLTP) on HDL metabolism. Atherosclerosis 2001; 155:269–81.[CrossRef][ISI][Medline]
74. Riemens SC, van Tol A, Sluiter WJ, Dullaart RPF. Plasma phospholipid transfer protein activity is related to insulin resistance: impaired acute lowering by insulin in obese Type II diabetic patients. Diabetologia 1998; 41:929–34.[CrossRef][ISI][Medline]
75. Riemens SC, van Tol A, Sluiter WJ, Dullaart RPF. Plasma phospholipid transfer protein activity is lowered by 24-h insulin and acipimox administration: blunted response to insulin in type 2 diabetic patients. Diabetes 1999; 48:1631–7.[Abstract]
76. Kaser S, Sandhofer A, Föger B, et al. Influence of obesity and insulin sensitivity on phospholipid transfer protein activity. Diabetologia 2001; 44:1111–17.[CrossRef][ISI][Medline]
77. Beulens JW, Sierksma A, van Tol A, Fournier N, van Gent T, Paul JL, Hendriks HF. Moderate alcohol consumption increases cholesterol efflux mediated by ABCA1. J Lipid Res 2004; 45:1716–23.
78. Brites F, Verona J, De Geitere C, Fruchart JC, Castro G, Wikinski R. Enhanced cholesterol efflux promotion in well-trained soccer players. Metabolism 2004; 53:1262–7.[Medline]
79. Zaratin AC, Quintao EC, Sposito AC, Nunes VS, Lottenberg AM, Morton RE, de Faria EC. Smoking prevents the intravascular remodeling of high-density lipoprotein particles: implications for reverse cholesterol transport. Metabolism 2004; 53:858–62.[Medline]
80. von Eckardstein A, Nofer JR, Assmann G. Acceleration of reverse cholesterol transport. Curr Opin Cardiol 2000; 15:348–54.[CrossRef][ISI][Medline]
81. Joyce C, Freeman L, Brewer HB Jr, Santamarina-Fojo S. Study of ABCA1 function in transgenic mice. Arterioscler Thromb Vasc Biol 2003; 23:965–71.
82. Vaisman BL, Lambert G, Amar M, Joyce C, Ito T, Shamburek RD, Cain WJ, Fruchart-Najib J, Neufeld ED, Remaley AT, Brewer HB Jr, Santamarina-Fojo S. ABCA1 overexpression leads to hyperalphalipoproteinemia and increased biliary cholesterol excretion in transgenic mice. J Clin Invest 2001; 108:303–9.[CrossRef][ISI][Medline]
83. Joyce CW, Amar MJ, Lambert G, Vaisman BL, Paigen B, Najib-Fruchart J, Hoyt RF, Jr., Neufeld ED, Remaley AT, Fredrickson DS, Brewer HB, Jr., Santamarina-Fojo S. The ATP binding cassette transporter A1 (ABCA1) modulates the development of aortic atherosclerosis in C57BL/6 and apoE-knockout mice. Proc Natl Acad Sci USA 2002; 99:407–12.
84. van Eck M, Bos IS, Kaminski WE, Orso E, Rothe G, Twisk J, Bottcher A, Van Amersfoort ES, Christiansen-Weber TA, Fung-Leung WP, Van Berkel TJ, Schmitz G. Leukocyte ABCA1 controls susceptibility to atherosclerosis and macrophage recruitment into tissues. Proc Natl Acad Sci USA 2002; 99:6298–303.
85. McNeish J, Aiello RJ, Guyot D, Turi T, Gabel C, Aldinger C, Hoppe KL, Roach ML, Royer LJ, de Wet J, Broccardo C, Chimini G, Francone OL. High density lipoprotein deficiency and foam cell accumulation in mice with targeted disruption of ATP-binding cassette transporter-1. Proc Natl Acad Sci USA 2000; 97:4245–50.
86. Aiello RJ, Brees D, Bourassa PA, Royer L, Lindsey S, Coskran T, Haghpassand M, Francone OL. Increased atherosclerosis in hyperlipidemic mice with inactivation of ABCA1 in macrophages. Arterioscler Thromb Vasc Biol 2002; 22:630–7.
87. Groen AK, Bloks VW, Bandsma RH, Ottenhoff R, Chimini G, Kuipers F. Hepatobiliary cholesterol transport is not impaired in Abca1-null mice lacking HDL. J Clin Invest 2001; 108:843–50.[CrossRef][ISI][Medline]
88. Dietschy JM, Turley SD. Control of cholesterol turnover in the mouse. J Biol Chem 2002; 277:3801–4.
89. Agellon LB, Walsh A, Hayek T, Moulin P, Jiang XC, Shelanski SA, Breslow JL, Tall AR. Reduced high density lipoprotein cholesterol in human cholesteryl ester transfer protein transgenic mice. J Biol Chem 1991; 266:10796–801.
90. Jiang XC, Masucci-Magoulas L, Mar J, Lin M, Walsh A, Breslow JL, Tall A. Down-regulation of mRNA for the low density lipoprotein receptor in transgenic mice containing the gene for human cholesteryl ester transfer protein: mechanism to explain accumulation of lipoprotein B particles. J Biol Chem 1993; 268:27406–12.
91. Plump AS, Masucci-Magoulas L, Bruce C, Bisgaier CL, Breslow JL, Tall AR. Increased atherosclerosis in apoE and LDL receptor gene knock-out mice as a result of human cholesteryl ester transfer protein transgene expression. Arterioscler Thromb Vasc Biol 1999; 19:1105–10.
92. Marotti KR, Castle CK, Boyle TP, Lin AH, Murray RW, Melchior GW. Severe atherosclerosis in transgenic mice expressing simian cholesteryl ester transfer protein. Nature 1993; 364:73–5.[CrossRef][Medline]
93. Hayek T, Masucci-Magoulas L, Jiang X, Walsh A, Rubin E, Breslow JL, Tall AR. Decreased early atherosclerotic lesions in hypertriglyceridemic mice expressing cholesteryl ester transfer protein transgene. J Clin Invest 1995; 96:2071–4.[ISI][Medline]
94. Kako Y, Masse M, Huang LS, Tall AR, Goldberg IJ. Lipoprotein lipase deficiency and CETP in streptozotocin-treated apoB-expressing mice. J Lipid Res 2002; 43:872–7.
95. Miyazaki A, Sakuma S, Morikawa W, Takiue T, Miake F, Terano T, Sakai M, Hakamata H, Sakamoto Y, Natio M, et al. Intravenous injection of rabbit apolipoprotein A-I inhibits the progression of atherosclerosis in cholesterol-fed rabbits. Arterioscler Thromb Vasc Biol 1995; 15:1882–8.
96. Tangirala RK, Tsukamoto K, Chun SH, Usher D, Pure E, Rader DJ. Regression of atherosclerosis induced by liver-directed gene transfer of apolipoprotein A-I in mice. Circulation 1999; 100:1816–22.
97. Navab M, Anantharamaiah GM, Hama S, Garber DW, Chaddha M, Hough G, Lallone R, Fogelman AM. Oral administration of an Apo A-I mimetic Peptide synthesized from D-amino acids dramatically reduces atherosclerosis in mice independent of plasma cholesterol. Circulation 2002; 105:290–2.
98. Navab M, Anantharamaiah GM, Reddy ST, Hama S, Hough G, Grijalva VR, Wagner AC, Frank JS, Datta G, Garber D, Fogelman AM. Oral D-4F causes formation of pre-beta high-density lipoprotein and improves high-density lipoprotein-mediated cholesterol efflux and reverse cholesterol transport from macrophages in apolipoprotein E-null mice. Circulation 2004; 109:3215–20.
99. Shah PK, Yano J, Reyes O, Chyu KY, Kaul S, Bisgaier CL, Drake S, Cercek B. High-dose recombinant apolipoprotein A-I(milano) mobilizes tissue cholesterol and rapidly reduces plaque lipid and macrophage content in apolipoprotein E-deficient mice. Potential implications for acute plaque stabilization. Circulation 2001; 103:3047–50.
100. Chiesa G, Monteggia E, Marchesi M, Lorenzon P, Laucello M, Lorusso V, Di Mario C, Karvouni E, Newton RS, Bisgaier CL, Franceschini G, Sirtori CR. Recombinant apolipoprotein A-I(Milano) infusion into rabbit carotid artery rapidly removes lipid from fatty streaks. Circ Res 2002; 90:974–80.
101. Oram JF, Wolfbauer G, Vaughan AM, Tang C, Albers JJ. Phospholipid transfer protein interacts with and stabilizes ATP-binding cassette transporter A1 and enhances cholesterol efflux from cells. J Biol Chem 2003; 278:52379–85.
102. van Haperen R, van Tol A, van Gent T, Scheek L, Visser P, van der Kamp A, Grosveld F, de Crom R. Increased risk of atherosclerosis by elevated plasma levels of phospholipid transfer protein. J Biol Chem 2002; 277:48938–43.