Future Therapeutic Directions in Reverse Cholesterol Transport

Despite a robust inverse association between high-density lipoprotein (HDL) cholesterol levels and atherosclerotic cardiovascular disease, the development of new therapies based on pharmacologic enhancement of HDL metabolism has proven challenging. Emerging evidence suggests that static measurement of HDL levels has inherent limitations as a surrogate for overall HDL functionality, particularly with regard to the rate of flux through the macrophage reverse cholesterol transport (RCT) pathway. Recent research has provided important insight into the molecular underpinnings of RCT, the process by which excess cellular cholesterol is effluxed from peripheral tissues and returned to the liver for ultimate intestinal excretion. This review discusses the critical importance and current strategies for quantifying RCT flux. It also highlights therapeutic strategies for augmenting macrophage RCT via three conceptual approaches: 1) improved efflux of cellular cholesterol via targeting the macrophage; 2) enhanced cholesterol efflux acceptor functionality of circulating HDL; and 3) increased hepatic uptake and biliary/intestinal excretion.     

Reverse cholesterol transport in type 2 diabetes mellitus

High-density lipoprotein (HDL) plays an important protective role against atherosclerosis, and the anti-atherogenic properties of HDL include the promotion of cellular cholesterol efflux and reverse cholesterol transport (RCT), as well as antioxidant, anti-inflammatory and anticoagulant effects. RCT is a complex pathway, which transports cholesterol from peripheral cells and tissues to the liver for its metabolism and biliary excretion. The major steps in the RCT pathway include the efflux of free cholesterol mediated by cholesterol transporters from cells to the main extracellular acceptor HDL, the conversion of free cholesterol to cholesteryl esters and the subsequent removal of cholesteryl ester in HDL by the liver. The efficiency of RCT is influenced by the mobilization of cellular lipids for efflux and the intravascular remodelling and kinetics of HDL metabolism. Despite the increased cardiovascular risk in people with type 2 diabetes, current knowledge on RCT in diabetes is limited. In this article, abnormalities in RCT in type 2 diabetes mellitus and therapeutic strategies targeting HDL and RCT will be reviewed.     

淋巴管参与胆固醇逆向转运

细胞需要胆固醇才能生存,但过量的胆固醇对细胞具有毒性,因此细胞需要调节胆固醇的稳态。细胞内胆固醇被转运到高密度脂蛋白载脂蛋白AI,会以胆固醇逆向转运的方式返回肝脏代谢。胆固醇逆向转运不仅是维持细胞胆固醇稳态所需的生理过程,而且对动脉粥样硬化发展起到潜在的抑制作用。目前的研究主要集中在细胞胆固醇流出的最初途径和最终代谢上,但关于胆固醇是如何离开血液却知之甚少。越来越多的研究表明,在胆固醇逆向转运过程中高密度脂蛋白需要通过淋巴管转运以返回到肝脏代谢。因此,研究高密度脂蛋白从血液流入外周组织的过程,以及它是怎样通过淋巴管转运对治疗动脉粥样硬化具有重要意义。本综述主要介绍淋巴管与胆固醇逆向转运之间的联系,为治疗动脉粥样硬化性心血管疾病提供新的策略。     

脂蛋白血管外循环与胆固醇逆向转运

胆固醇逆向转运是机体周围组织细胞胆固醇转运至肝脏转化排泄的重要生理过程，它在维持机体胆固醇平衡和防止动脉粥样硬化的发生和发展过程中起着重要的作用。脂蛋白是胆固醇的载体，血浆脂蛋白可以透过血管壁进入间质组织，通过与组织细胞直接接触接受细胞释出的胆固醇，再经淋巴液或直接返回血浆，并运至肝脏代谢。因此，脂蛋白血管外循环是胆固醇逆向转运重要组成部分。研究脂蛋白血管外循环的过程、特征以及代谢变化的规律，对心血管病的防治具有重要的理论和实践价值。     

New insights into the regulation of HDL metabolism and reverse cholesterol transport

The metabolism of high-density lipoproteins (HDL), which are inversely related to risk of atherosclerotic cardiovascular disease, involves a complex interplay of factors regulating HDL synthesis, intravascular remodeling, and catabolism. The individual lipid and apolipoprotein components of HDL are mostly assembled after secretion, are frequently exchanged with or transferred to other lipoproteins, are actively remodeled within the plasma compartment, and are often cleared separately from one another. HDL is believed to play a key role in the process of reverse cholesterol transport (RCT), in which it promotes the efflux of excess cholesterol from peripheral tissues and returns it to the liver for biliary excretion. This review will emphasize 3 major evolving themes regarding HDL metabolism and RCT. The first theme is that HDL is a universal plasma acceptor lipoprotein for cholesterol efflux from not only peripheral tissues but also hepatocytes, which are a major source of cholesterol efflux to HDL. Furthermore, although efflux of cholesterol from macrophages represents only a tiny fraction of overall cellular cholesterol efflux, it is the most important with regard to atherosclerosis, suggesting that it be specifically termed macrophage RCT. The second theme is the critical role that intravascular remodeling of HDL by lipid transfer factors, lipases, cell surface receptors, and non-HDL lipoproteins play in determining the ultimate metabolic fate of HDL and plasma HDL-c concentrations. The third theme is the growing appreciation that insulin resistance underlies the majority of cases of low HDL-c in humans and the mechanisms by which insulin resistance influences HDL metabolism. Progress in our understanding of HDL metabolism and macrophage reverse cholesterol transport will increase the likelihood of developing novel therapies to raise plasma HDL concentrations and promote macrophage RCT and in proving that these new therapeutic interventions prevent or cause regression of atherosclerosis in humans.     

Dynamics of reverse cholesterol transport: protection against atherosclerosis

This review considers the antiatherogenic function of high density lipoprotein (HDL) from the point of view of its dynamics within the sequential steps of reverse cholesterol transport (RCT). It is postulated that the efficiency of cholesterol flux through the RCT pathways is clinically more relevant than the HDL cholesterol concentration. The particular role of pre-beta(1)-HDL is reviewed drawing attention to the relationship between its concentration and the flux of cholesterol through the RCT system.     

Thyroid hormones and thyroid hormone receptors: effects of thyromimetics on reverse cholesterol transport

Reverse cholesterol transport (RCT) is a complex process which transfers cholesterol from peripheral cells to the liver for subsequent elimination from the body via feces. Thyroid hormones (THs) affect growth, develop- ment, and metabolism in almost all tissues. THs exert their actions by binding to thyroid hormone receptors (TRs). There are two major subtypes of TRs, TRα and TRβ, and several isoforms (e.g. TRα1, TRα2, TRβ1, and TRβ2). Activation of TRα1 affects heart rate, whereas activation of TRβ1 has po...     

High density lipoproteins and arteriosclerosis. Role of cholesterol efflux and reverse cholesterol transport

High density lipoprotein (HDL) cholesterol is an important risk factor for coronary heart disease, and HDL exerts various potentially antiatherogenic properties, including the mediation of reverse transport of cholesterol from cells of the arterial wall to the liver and steroidogenic organs. Enhancement of cholesterol efflux and of reverse cholesterol transport (RCT) is considered an important target for antiatherosclerotic drug therapy. Levels and composition of HDL subclasses in plasma are regulated by many factors, including apolipoproteins, lipolytic enzymes, lipid transfer proteins, receptors, and cellular transporters. In vitro experiments as well as genetic family and population studies and investigation of transgenic animal models have revealed that HDL cholesterol plasma levels do not necessarily reflect the efficacy and antiatherogenicity of RCT. Instead, the concentration of HDL subclasses, the mobilization of cellular lipids for efflux, and the kinetics of HDL metabolism are important determinants of RCT and the risk of atherosclerosis.     

Role of Phospholipid Transfer Protein in High-Density Lipoprotein– Mediated Reverse Cholesterol Transport

Reverse cholesterol transport (RCT) describes the process whereby cholesterol in peripheral tissues is transported to the liver where it is ultimately excreted in the form of bile. Given the atherogenic role of cholesterol accumulation within the vessel intima, removal of cholesterol through RCT is considered an anti-atherogenic process. The major constituents of RCT include cell membrane– bound lipid transporters, plasma lipid acceptors, plasma proteins and enzymes, and lipid receptors of liver cell membrane. One major cholesterol acceptor in RCT is high-density lipoprotein (HDL). Both the characteristics and level of HDL are critical determinants for RCT. It is known that phospholipid transfer protein (PLTP) impacts both HDL cholesterol level and biological quality of the HDL molecule. Recent data suggest that PLTP has a site-specific variation in its function. Moreover, the RCT pathway also has multiple steps both in the peripheral tissues and circulation. Therefore, PLTP may influence the RCT pathway at multiple levels. In this review, we focus on the potential role of PLTP in RCT through its impact on HDL homeostasis. The relationship between PLTP and RCT is expected to be an important area in finding novel therapies for atherosclerosis.     

A new framework for reverse cholesterol transport: non-biliary contributions to reverse cholesterol transport

Reduction of low-density lipoprotein-cholesterol through statin therapy has only modestly decreased coronary heart disease (CHD)-associated mortality in developed countries, which has prompted the search for alternative therapeutic strategies for CHD. Major efforts are now focused on therapies that augment high-density lipoprotein (HDL)-mediated reverse cholesterol transport (RCT), and ultimately increase the fecal disposal of cholesterol. The process of RCT has long been thought to simply involve HDL-media...     

Cellular processes in atherogenesis: potential targets of Ca2+ channel blockers.

Atherosclerosis is characterized by increased endothelial permeability, monocyte infiltration, intimal smooth muscle cell (SMC) proliferation, platelet aggregation and the accumulation of lipids, calcium and extracellular matrix components in the vessel wall. In various animal studies and recently in humans it could be established that Ca2+ channel blockers delayed the progression of the atherosclerotic process at the stage of early lesions. This review surveys the interaction of Ca2+ channel blockers with various membrane proteins (purinergic receptors, nucleoside transporter, peripheral benzodiazepine receptors, multi-drug resistance protein) which are involved in signal transduction and their potential impact on the observed antiatherosclerotic effects. Although the precise mechanisms have yet to be fully elucidated, it has been clearly shown that these drugs inhibit smooth muscle cell proliferation and migration, improve cellular lipoprotein metabolism in vascular cells, alter phospholipid turnover, decrease platelet adhesion in the vessel wall, reduce extracellular matrix synthesis and protect against radical induced cell damage. Most of these effects are independent of Ca2+ flux across voltage-operated Ca2+ channels. However, all these processes are relevant to the pathogenesis of atherosclerosis and therefore the elucidation of the antiatherogenic mechanisms of Ca2+ channel blockers at the cellular level is of great interest. The future development of Ca2+ channel blockers with altered molecular structures optimized for their antiatherosclerotic targets may provide a useful tool in the therapy of atherosclerosis and risk factor intervention. The protective mechanisms are related to a stabilization of cell membrane integrity, the modulation of secretory activities and cell/cell communication processes rather than to a lowering of plasma lipoprotein levels.     

Reverse cholesterol transport revisited: contribution of biliary versus intestinal cholesterol excretion

Reverse cholesterol transport (RCT) is usually defined as high-density lipoprotein-mediated transport of excess cholesterol from peripheral tissues, including cholesterol-laden macrophages in vessel walls, to the liver. From the liver, cholesterol can then be removed from the body via secretion into the bile for eventual disposal via the feces. According to this paradigm, high plasma high-density lipoprotein levels accelerate RCT and hence are atheroprotective. New insights in individual steps of the RCT pathway, in part derived from innovative mouse models, indicate that the classical concept of RCT may require modification.     

AIBP: A Novel Molecule at the Interface of Cholesterol Transport,Angiogenesis, and Atherosclerosis

Cardiovascular disease, which is often driven by hypercholesterolemia and subsequent coronary atherosclerosis, is the number-one cause of morbidity and mortality in the United States. Based on long-term epidemiological studies, high-density lipoprotein cholesterol (HDL-C) levels are inversely correlated with risk for coronary artery disease (CAD). HDL-mediated reverse cholesterol transport (RCT) is responsible for cholesterol removal from the peripheral tissues and return to the liver for final elimination.1 In atherosclerosis, intraplaque angiogenesis promotes plaque growth and increases plaque vulnerability. Conceivably, the acceleration of RCT and disruption of intraplaque angiogenesis would inhibit atherosclerosis and reduce CAD. We have identified a protein called apoA-I binding protein (AIBP) that augments HDL functionality by accelerating cholesterol efflux. Furthermore, AIBP inhibits vascular endothelial growth factor receptor 2 activation in endothelial cells and limits angiogenesis.2 The following discusses the prospect of using AIBP as a novel therapeutic approach for the treatment of CAD.     

What is so special about apolipoprotein AI in reverse cholesterol transport?

An initial step in reverse cholesterol transport is the movement of unesterified cholesterol from peripheral cells to high-density lipoproteins (HDLs). This transfer usually occurs in extracellular spaces, such as the subendothelial space of a vessel wall, and is promoted by the interaction of lipid-free or lipid-poor apolipoprotein (apo)AI with ATP binding cassette A1 cellular transporters on macrophages (MPhi). Because HDL does not interact with MPhi ATP binding cassette A1 and apoAI is not synthesized by macrophages, this apoAI must be generated from spherical HDL. In this brief review, we propose that spherical apoAI is derived from HDL by remodeling events that are accomplished by proteins secreted by cholesteryl ester-loaded foam cells, including the lipid transfer proteins, phospholipid transfer protein, and cholesteryl ester transfer protein, and the triglyceride hydrolases hepatic lipase and lipoprotein lipase.     

Effects of inflammation on cholesterol metabolism: Impact on systemic lupus erythematosus

Inflammation and dysregulated cholesterol metabolism are key components in the pathogenesis of atherosclerosis. Premature atherosclerosis is a characteristic feature of systemic lupus erythematosus. Although the cellular and molecular mechanisms underlying accelerated atherogenesis in lupus are not thoroughly understood, inflammation associated with the rheumatic disease state may promote atherosclerosis. Increasing evidence indicates that the systemic inflammatory load in lupus disrupts cholesterol homeostasis, increasing vulnerability to cholesterol accumulation in cells of the artery wall, including macrophages and endothelium. The relationship between the inflammatory state and dyslipidemia in lupus is complex, involving lipoproteins, cholesterol transporters, scavenger receptors, and oxysterols. The impact of lupus on each of these components of the cholesterol flux pathways is discussed. The formation of autoantibodies against epitopes within lipoprotein particles and their controversial role in atherogenesis is addressed.     

ABCA1 Agonist Mimetic Peptide CS-6253 Induces Microparticles Release From Different Cell Types by ABCA1-Efflux–Dependent Mechanism

BackgroundSmall peptides based on the C-terminal domain of apo E have recently been proposed as ATP-binding cassette transporter A1 (ABCA1) agonist with therapeutic potential. Previous work has shown that a novel synthetic peptide, CS-6253, acts synergistically with apolipoprotein A-I or alone to generate high-density lipoprotein (HDL) particles; we have also shown that cells can release microparticles (50-350 nm in apparent diameter) in an ABCA1- and apolipoprotein A-I-dependent manner. The purpose of this study was to explore the ability of a novel synthetic peptide CS-6253 to induce microparticle release from various cell lines in the process of HDL biogenesis.MethodsThe effects of CS-6253 on microparticle formation through the ABCA1 transporter were examined in vitro using cell-based systems and pharmacologic manipulations.ResultsIn cell-based systems combined with fast performance liquid chromatography and nano-sight-tracking analysis, we show that ABCA1 and CS-6253 mediate and increase the production of microparticles containing cholesterol. CS-6253 in baby hamster kidney cells not expressing ABCA1 (baby hamster kidney mock cells) did not alter cholesterol removal across the plasma membrane in the absence of ABCA1 expression even at high concentrations. We report that CS-6253 is not cytotoxic.ConclusionsThe present study shows that CS-6253 generates cholesterol containing microparticles with size heterogeneity (100-350 nm) in an ABCA1-dependent manner. We show that microparticles contribute to cell cholesterol efflux from monocyte-macrophage cells. At high doses, CS-6253 is not able to extract cholesterol from cells not expressing ABCA1, indicating that CS-6253 requires ABCA1 cooperation for cholesterol mobilization. We conclude that CS-6253 is an ABCA1 agonist peptide that promotes cellular cholesterol efflux through HDL biogenesis and microparticle formation.     

高密度脂蛋白逆转运胆固醇的分子生物学基础

高密度脂蛋白(HDL)能够将胆固醇从泡沫细胞中转运到肝脏,代谢转化为胆汁排出体外,进而产生抗动脉粥样硬化作用,称之为HDL的胆固醇逆转运(RCT)。因此,如何提高HDL浓度并促进HDL的功能,充分发挥其抗动脉粥样硬化的功能,成为近年来研究的热点。但研究显示单纯升高HDLC并未发现有明显的临床效果,揭示了HDL功能的复杂性。因此有必要进行系统的回顾HDL的分子结构、合成、代谢等,重新认识其RCT功能的分子生物学基础,为进一步研究HDL的RCT功能提供理论支撑。     

Lipoprotein physiology and its relationship to atherogenesis

The major plasma lipids, cholesterol, triglycerides, and phospholipids are transported as components of macromolecular complexes called lipoproteins. The major lipoprotein classes include the chylomicrons, which transport dietary lipids to the peripheral tissues and the liver; very low density and low density lipoproteins, which transport endogenously synthesized lipids from the liver to peripheral tissues; and high density lipoproteins, which appear to facilitate the reverse transport of cholesterol from peripheral tissues to the liver. The rates of synthesis and catabolism of the major lipoprotein classes are regulated, to a large degree, by one or more proteins, called apoproteins, that reside on the surface of the lipoproteins. This article describes normal lipoprotein metabolism and includes discussions of the role of abnormalities in lipoprotein transport in the atherogenic process.     

B-Type natriuretic peptide inhibited angiotensin II-stimulated cholesterol biosynthesis, cholesterol transfer, and steroidogenesis in primary human adrenocortical cells

In this study, we demonstrate that B-type natriuretic peptide (BNP) opposed angiotensin II (Ang II)-stimulated de novo cholesterol biosynthesis, cellular cholesterol uptake, cholesterol transfer to the inner mitochondrial membrane, and steroidogenesis, which are required for biosynthesis of steroid hormones such as aldosterone and cortisol in primary human adrenocortical cells. BNP dose-dependently stimulated intracellular cGMP production with an EC(50) of 11 nm, implying that human adrenocortical cells express the guanylyl cyclase A receptor. cDNA microarray and real-time RT-PCR analyses revealed that BNP inhibited Ang II-stimulated genes related to cholesterol biosynthesis (acetoacetyl coenzyme A thiolase, HMG coenzyme A synthase 1, HMG coenzyme A reductase, isopentenyl-diphosphate Delta-isomerase, lanosterol synthase, sterol-4C-methyl oxidase, and emopamil binding protein/sterol isomerase), cholesterol uptake from circulating lipoproteins (scavenger receptor class B type I and low-density lipoprotein receptor), cholesterol transfer to the inner mitochondrial membrane (steroidogenic acute regulatory protein), and steroidogenesis (ferredoxin 1,3beta-hydroxysteroid dehydrogenase, glutathione transferase A3, CYP19A1, CYP11B1, and CYP11B2). Consistent with the microarray and real-time PCR results, BNP also blocked Ang II-induced binding of (125)I-labeled low-density lipoprotein and (125)I-labeled high-density lipoprotein to human adrenocortical cells. Furthermore, BNP markedly inhibited Ang II-stimulated release of estradiol, aldosterone, and cortisol from cultured primary human adrenocortical cells. These findings demonstrate that BNP opposes Ang II-induced steroidogenesis via multiple steps from cholesterol supply and transfer to the final formation of steroid hormones. This study provides new insights into the cellular mechanisms by which BNP modulates Ang II-induced steroidogenesis in the adrenal gland.