胆固醇逆向转运关键蛋白介导药物和小分子调控脂代谢的机制研究

胆固醇逆向转运(RCT)异常导致脂代谢紊乱是动脉粥样硬化发病重要环节,探讨介导RCT的关键蛋白在脂代谢中的作用及调控机制对阐明动脉粥样硬化发病的分子机制具有重要意义。本期专题收集的论文探讨了利拉鲁肽、苦瓜素以及生长分化因子11对细胞胆固醇流出及介导RCT中关键蛋白三磷酸腺苷结合盒转运体A1(ABCA1)、ABCG1和B类Ⅰ型清道夫受体表达的影响,分别从不同角度阐释RCT关键蛋白参与药物或小分子物质调控胆固醇流出的分子机制。     

炎症调控胆固醇逆向转运的机制研究

胆固醇逆向转运(RCT)是促进细胞内胆固醇流出并转运至肝脏进行代谢的过程,其功能异常在动脉粥样硬化(As)的发生发展中起着关键作用。糖尿病、肥胖等慢性代谢性炎症疾病促进As的进展,而体内炎症、脂肪因子参与调控RCT是其重要的调控机制之一。本期专题收集的研究论文和综述探讨了糖基化终末产物Nε-羧甲基赖氨酸、核因子κB(NF-κB)、脂肪因子Visfatin等对细胞内胆固醇流出及介导RCT中关键蛋白三磷酸腺苷结合盒转运体A1、Sortilin、酯酰辅酶A:胆固醇酰基转移酶(ACAT)等表达的影响,从不同角度阐释慢性代谢性炎症疾病调控RCT和心血管疾病发生发展的分子机制。     

靶向肝X受体的抗动脉粥样硬化药物研究进展

肝X受体(LXR)是机体胆固醇稳态维持的重要调控因子,通过调控下游靶基因表达,参与调节各组织中的胆固醇代谢。LXR激动剂能够促进胆固醇逆向转运,发挥抗动脉粥样硬化作用,具有潜在治疗心血管疾病的作用。本文围绕近年来新型LXR激动剂,从不同来源、特点和作用机制等角度对其发挥抗动脉粥样硬化作用进行综述。     

胆固醇流出调节蛋白和胆固醇逆向转运与动脉粥样硬化

胆固醇流出调节蛋白(cholesterol efllux regulatory protein，CERP)是由腺苷三磷酸结合暗盒运输器l(ATP binding cassette transporter l，ABCl)基因编码的蛋白质，在胆固醇的逆向转运中起重要的作用。ABCl基因突变导致其编码的CERP异常，引起胆固醇逆向转运障碍，胆固醇在外周组织细胞聚集，从而可导致血脂异常，动脉粥样硬化等一系列临床病理改变。细胞内脂质，核受体PPARγ，LXR、RXR对ABC1蛋白的表达具有调控作用，这些研究结果为新药开发，动脉粥样硬化以及冠心病、脑卒中的治疗开辟了新的前景。     

参与负性调控胆固醇逆向转运的microRNA

加强胆固醇逆向转运(RCT)具有抗动脉粥样硬化作用,microRNA(miRNA)参与多种生物学过程的调控,研究发现多个miRNA参与RCT调控,其通过对RCT的关键蛋白ATP结合盒转运体A1(ABCA1)和受体B类Ⅰ型清道夫受体(SR-BⅠ)的调控而发挥作用。目前已发现多种miRNA可抑制ABCA1和SR-BⅠ蛋白表达水平,进而抑制RCT和胆固醇流出,本文拟就负性调控RCT的miRNA进行综述。     

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。     

高密度脂蛋白在心血管代谢风险中的研究

心血管代谢风险与动脉粥样硬化密不可分。临床流行病学已经证实高密度脂蛋白胆固醇水平与心血管事件呈负相关。高密度脂蛋白胆固醇通过促进胆固醇的逆向转运、抑制低密度脂蛋白胆固醇的氧化、抑制黏附因子的表达、改善血管内皮功能等途径抑制动脉粥样硬化的进展。高密度脂蛋白的功能比水平更为重要,载脂蛋白A1是维持高密度脂蛋白结构稳定性及功能的重要蛋白。改善生活方式升高高密度脂蛋白血浆水平的同时,近年来的研究进展中调控载脂蛋白A1的药物起到了一定的效果。     

高密度脂蛋白在心血管代谢风险中的研究

心血管代谢风险与动脉粥样硬化密不可分。临床流行病学已经证实高密度脂蛋白胆固醇水平与心血管事件呈负相关。高密度脂蛋白胆固醇通过促进胆固醇的逆向转运、抑制低密度脂蛋白胆固醇的氧化、抑制黏附因子的表达、改善血管内皮功能等途径抑制动脉粥样硬化的进展。高密度脂蛋白的功能比水平更为重要,载脂蛋白A1是维持高密度脂蛋白结构稳定性及功能的重要蛋白。改善生活方式升高高密度脂蛋白血浆水平的同时,近年来的研究进展中调控载脂蛋白A1的药物起到了一定的效果。     

小凹及小凹蛋白1：胆固醇逆向转运与炎症应答的共同分子平台

脂质紊乱和炎症反应在动脉粥样硬化的发生发展中发挥了重要的作用。其中胆固醇的逆向转运能力是决定动脉粥样硬化进程与转归的关键。大量文献及研究结果显示,小凹以及小凹蛋白1既在荷脂细胞胆固醇流出中发挥转运中心和关键分子作用,也在炎症反应中发挥介导抗炎的信号转导作用。因此,小凹以及小凹蛋白1可能是荷脂细胞胆固醇逆向转运和炎症应答的共同分子平台。     

部分天然药物通过调节肠道胆固醇代谢途径防治心血管疾病的作用机制

肠道胆固醇代谢与心血管疾病的发生发展密切相关,调控肠道胆固醇代谢平衡可有效降低心血管事件。天然药物通过调控肠道胆固醇的吸收与转运、调节菌群平衡等途径有效改善肠道胆固醇代谢水平。文章对近年来天然药物调控肠道胆固醇代谢抑制心血管疾病的作用与机制进行了综述,以期为脂代谢紊乱所致心血管疾病的防治提供借鉴。     

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.     

High-Density Lipoprotein Processing and Premature Cardiovascular Disease

High plasma concentrations of low-density lipoprotein-cholesterol (LDL-C) are a well-accepted risk factor for cardiovascular disease (CVD), and the statin class of hypolipidemic drugs has emerged as an effective means of lowering LDL-C and reducing CVD risk. In contrast, the role of plasma high-density lipoproteins (HDL) in protection against atherosclerotic vascular disease is the subject of considerable controversy. Although the inverse correlation between plasma HDL-C and CVD is widely acknowledged, reduction of CVD risk by interventions that increase HDL-C have not been uniformly successful. Several studies of large populations have shown that the first step in reverse cholesterol transport (RCT), the transfer of cholesterol from the subendothelial space of the arterial wall via the plasma compartment to the liver for disposal, is impaired in patients with CVD. Here we review HDL function, the mechanisms by which HDL supports RCT, and the role of RCT in preventing CVD.     

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.     

High-density lipoproteins from human alcoholics exhibit impaired reverse cholesterol transport function

We have previously shown that chronic alcohol consumption leads to inhibition of sialylation of apolipoprotein E (apo E) that results in its impaired binding to high-density lipoprotein (HDL) molecule. Because apo E plays a major role in reverse cholesterol transport (RCT), we speculated that ethanol-mediated formation of HDL molecules without apo E may affect the RCT process. Therefore, we have investigated whether the RCT function of HDL is affected in chronic alcoholics with or without liver disease compared with nondrinkers. HDL was isolated from fasting plasma of normal subjects, n = 9 (nondrinkers), chronic alcoholics, n = 8 (ALC), and chronic alcoholics with liver disease, n = 6 (ALD). A portion of HDL sample from each subject was evaluated for its cholesterol efflux capacity from [3H]cholesterol oleate preloaded mouse macrophages. The remaining portion of each HDL sample was labeled with [3H]cholesterol oleate and evaluated for its ability to deliver cholesterol to the liver using HepG2 cells in culture. Cholesterol efflux capacity of HDLs was decreased by 83% (P < .0002) in alcoholics without liver disease and by 84% (P < .0006) in alcoholics with liver disease compared with the HDLs from nondrinkers. The capacities of HDLs to deliver cholesterol to the liver were decreased by 54% (P < .005) in alcoholics without liver disease and by 64% (P < .005) in alcoholics with liver disease compared with the HDLs from nondrinkers. The fact that further complications by liver disease in alcoholic subjects did not significantly exacerbate the extent of impairment in RCT function of HDL suggest that alcohol per se is responsible for its deleterious effects on RCT. Significantly, plasma HDL apo E concentration relative to that of apo A1 (apo E/apo A1 ratio) was also decreased by 31% to 32% (P < .0005) in alcoholics without or with liver disease compared with nondrinkers. It is therefore concluded that chronic alcohol consumption adversely affects the RCT function of HDL by altering its association with apo E due to ethanol-induced desialylation of apo E.     

Gallstone formation. Local factors

Bile supersaturation is necessary for cholesterol gallstones to form. Not all people with supersaturated bile form gallstones, however, and additional factors must be present. The role of pronucleating substances has been extensively studied. Of these, proteins, especially mucin, are best understood. Mucin is secreted by the gallbladder epithelium and may act as a nidus for crystal nucleation. Other proteins that may act as pronucleators include alpha 1-acid glycoprotein, alpha 1-antichymotrypsin, phospholipase C, and a small calcium binding protein. The role of antinucleating factors is less well understood. Certain drugs, including octreotide and ceftriaxone, may also predispose to stone formation. Another local factor is gallbladder stasis, a well-known risk factor for pigment stone formation. More recent research has focused on the role of bacterial infection, which has long been believed to be a factor in pigment gallstone formation. Newer data also support a role for infection in cholesterol gallstone pathogenesis. Additionally, genetic factors that may predispose a patient to cholesterol gallstones have been identified in mice and in humans.     

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.     

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.     

Reverse cholesterol transport: from classical view to new insights

Cholesterol is of vital importance for the human body. It is a constituent for most biological membranes, it is needed for the formation of bile salts, and it is the pre- cursor for steroid hormones and vitamin D. However, the presence of excess cholesterol in cells, and in particular in macrophages in the arterial vessel wall, might be harmful. The accumulation of cholesterol in arteries can lead to atherosclerosis, and in turn, to other cardiovascular diseases. The route that is primarily thought to be re...     

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.     

Expression of cholesteryl ester transfer protein in human atherosclerotic lesions and its implication in reverse cholesterol transport.

Reverse cholesterol transport (RCT) is the major protective system against atherosclerosis. In this system, cholesteryl ester transfer protein (CETP) is known to facilitate the transfer of neutral lipids between lipoproteins in plasma. We reported the pathophysiological significance of CETP by clinical studies with genetic CETP deficiency, showing that this protein plays a crucial role in the RCT system. However, information about the expression of this protein in the initial step of RCT, macrophages (Mphi) in the blood vessels, is still very limited. In the present study, we have performed immunohistochemical analyses on the expression of CETP in human atherosclerotic lesions. The immunoreactive mass of CETP was abundantly detected in foam cells in human aortic and coronary atherosclerotic lesions, but not in the normal arterial wall. A double immunostaining showed that the majority of CETP-positive foam cells were derived from Mphi and a minor population appeared to derive from smooth muscle cells. Transient transfection of CETP cDNA into COS-7 cells showed that high density lipoprotein (HDL)-mediated efflux of free cholesterol from the cells expressing CETP was much higher than that from mock-transfected cells, while uptake of HDL-lipids was not affected in cells transfected with CETP cDNA. Efflux of free cholesterol from the Mphi obtained from CETP deficiency was significantly decreased compared with that from normal subjects. These data indicate that CETP is expressed in Mphi in the atherosclerotic lesions and may possess an anti-atherogenic function to remove cholesterol from the cells, suggesting another role of CETP at the initial step of RCT.