胆固醇逆向转运与动脉粥样硬化的研究进展

血脂异常是动脉粥样硬化的一个重要危险因素。大量的流行病学研究和临床资料显示 ,血浆高密度脂蛋白胆固醇 (HDL -C)水平与动脉粥样硬化的发生呈明显负相关。基础研究发现 ,虽然HDL的抗动脉粥样硬化作用可涉及多种机制 ,如减轻脂蛋白的氧化等 ,但其最主要的作用机制在于参与胆固醇的逆向转运 (reversecholesteroltransport ,RCT)过程。体内肝外组织缺乏使类固醇激素降解为可排泄的胆酸形式的酶 ,除提供生理需要外 ,外周组织中多余的胆固醇均通过HDL运回肝脏代谢 ,这一生理过程称为RCT。RCT的初始步骤是细胞内的游离胆固醇和磷脂经A…     

疾病状态下高密度脂蛋白的功能缺陷

在炎症、脂质紊乱以及代谢性疾病中,高密度脂蛋白(HDL)抗动脉粥样硬化特性会受到影响。这种功能的损伤反映在HDL的组成、代谢及相关的生物学活性上。HDL的功能缺陷会影响血管内HDL代谢,使胆固醇逆转运、抗炎及抗氧化能力下降。HDL功能缺陷和浓度降低的共同作用,加速了动脉粥样硬化的发生。对HDL功能异常的检测有助于进一步了解动脉粥样硬化发生的机制,针对HDL功能和数量的治疗有希望在未来成为抗动脉粥样硬化治疗的新靶点。     

对卵磷脂胆固醇酰基转移酶的全新认识

卵磷脂胆固醇酰基转移酶(lecithin cholesterol acyl transferase,LCAT)作为参与胆固醇逆转运(reverse cholesterol transport,RCT)、高密度脂蛋白(HDL)等脂蛋白代谢的关键酶,在抗动脉粥样硬化(atherosclerosis,AS)的防御系统中起着重要作用。对其的进一步研究将会提高对CHD发生、发展的认识,为CHD的诊治带来新的思路。     

磷脂转运蛋白在高密度脂蛋白代谢和胆固醇逆向转运中的生物学作用

磷脂转运蛋白(PLTP)活性与糖尿病、肥胖、动脉粥样硬化等疾病明显相关的作用机制主要与其参与脂蛋白代谢有关。其中最引人注目的是PLTP在高密度脂蛋白(HDL)代谢和胆固醇逆向转运(RCT)中发挥的复杂生物学作用。PLTP可否通过影响HDL和RCT而发挥对动脉粥样硬化的作用?本文通过近年的文献复习并结合我们的相关工作与读者一同寻找答案和线索。     

Preβ-1高密度脂蛋白与心血管疾病关系的研究进展

动脉粥样硬化是心血管疾病重要的病理生理基础,延缓和防治动脉粥样硬化对于减少和降低心血管疾病的发病率及死亡率具有重要意义。HDL(high density lipoprotein,HDL)通过参与介导胆固醇逆向转运(reverse cholesterol transport,RCT）在抗动脉粥样硬化的形成和进展中发挥了重要作用。Preβ-1高密度脂蛋白（Prebeta-1 high density lipoprotein,preβ1-HDL）作为HDL的一种亚类,是外周细胞移出胆固醇的最初接受体,直接参与了胆固醇逆向转运的起始步骤,并在随后胆固醇酯化及转运中起着重要作用。本文就preβ1-HDL的结构、代谢及其与心血管病的关系作一简要综述。     

“失功能”HDL与动脉粥样硬化

高密度脂蛋白(HDL)具有介导胆固醇逆向转运、抗氧化、抗炎、保护内皮等功能而被公认为动脉粥样硬化的重要防御因素。但在炎症、代谢性疾病状态下,HDL发生组分改变、氧化或修饰,可转化为致动脉粥样硬化的"失功能"HDL,进而与心血管事件发生率的增加有关。本文概述"失功能"HDL的组成与功能特征,旨在为动脉粥样硬化性心血管疾病提供新的诊治手段。     

胆固醇逆向转运与动脉粥样硬化的研究进展

血脂异常是动脉粥样硬化的一个重要危险因素.大量的流行病学研究和临床资料显示,血浆高密度脂蛋白胆固醇(HDL-C)水平与动脉粥样硬化的发生呈明显负相关.基础研究发现,虽然HDL的抗动脉粥样硬化作用可涉及多种机制,如减轻脂蛋白的氧化等,但其最主要的作用机制在于参与胆固醇的逆向转运(reverse cholesterol transport, RCT)过程.     

靶向“失功能性”高密度脂蛋白的研究进展

高密度脂蛋白(HDL)是血浆中携运胆固醇的一类主要脂蛋白,正常情况下,HDL具有介导胆固醇逆向转运(RCT)、抗氧化及抗炎、抑血栓形成、促内皮修复等调节血管功能的作用,是机体重要的动脉粥样硬化(As)防御因素。但HDL是在起源、大小、组成及功能上表现极不均一性的脂蛋白颗粒,同时炎症、氧化应激、血脂紊乱、高糖等环境下可引起HDL结构及组分的     

清道夫受体BI与动脉粥样硬化

清道夫受体B族I型(SR-BI)是细胞膜上首个被定义为高密度脂蛋白(HDL)受体的糖蛋白,其介导细胞选择性摄取高密度脂蛋白胆固醇(HDLC),影响细胞胆固醇平衡、炎症表型。肝脏SR-BI在胆固醇逆向转运中扮演重要角色,而与HDL的代谢及其抗动脉粥样硬化(As)作用密切相关,并且已发现人类存在SR-BI基因多态性。本文重点从SR-BI结构、功能、调节及其对As的作用进行综述。     

高密度脂蛋白靶向防治动脉粥样硬化新进展

许多随机临床试验已经明确,他汀类药物因为可以降低低密度脂蛋白胆固醇水平并轻度增加高密度脂蛋白胆固醇(HDLC)水平,已经成为防治动脉粥样硬化(As)疾病的主要标准疗法。高密度脂蛋白(HDL)颗粒介导的胆固醇逆转运(RCT)途径具有抗As的作用。目前HDL靶向治疗的重要途径已经不是升高HDLC水平,更多的是通过改善HDL功能,增强血浆胆固醇的清除,以及预防和减轻与As有关的炎症。胆固醇酯转移蛋白抑制剂可增加正常或低HDLC患者的HDLC水平;肝X受体激动剂可通过增加RCT减少As;使用重组HDL的HDL治疗在动物模型中显著有效;在细胞以及动物模型中研究发现,通过干预某些基因靶点,可使HDLC的水平和HDL功能得到改善。回顾相关文献,我们认为:HDL靶向治疗有防治As的潜力,可能对心血管疾病患者有效。     

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.     

Desialylation of human apolipoprotein E decreases its binding to human high-density lipoprotein and its ability to deliver esterified cholesterol to the liver.

Apolipoprotein E (apoE) plays a significant role in the delivery of high-density lipoprotein (HDL) cholesterol to the liver via the apoB/E receptor. The roles of the apoE sialylation status in its association with HDL and in the reverse cholesterol transport (RCT) function of HDL have not been well defined. Furthermore, long-term ethanol treatment impairs apoE sialylation and leads to its decreased content in HDL. Therefore, we investigated the association of either sialo apoE (SapoE) or desialo apoE (DSapoE) with HDL and its effect on the RCT function of HDL. The dextran sulfate precipitation method showed that [125I]DSapoE binding to HDL was 27.3% (P < .02) to 35.5% (P < .001) lower versus [125I]SapoE. Scatchard analysis of the specific binding data showed that [125I]SapoE had 11.2 times more affinity for HDL than [125I]DSapoE based on size-exclusion chromatography (Kd = 89.7 v 1,010 nmol/L). Similarly, [1251]HDL had 4.5 times more affinity for SapoE compared with DSapoE based on solid-phase binding (Kd = 21.9 v 104.4 nmol/L). Furthermore, esterified cholesterol uptake from reconstituted HDL particles (rHDLs) by HepG2 cells increased over basal uptake up to 153% when rHDLs contained SapoE, versus only 37% with DSapoE. Enzymatic resialylation of DSapoE completely restored its HDL-binding and RCT properties, identical to those of SapoE. It is therefore concluded that desialylation of apoE decreases its binding to plasma HDL, leading to an impaired RCT function.     

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.     

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.     

Functional heterogeneity of high density lipoproteins and its future therapeutic indication

The atheroprotective effect of HDL is well-established, the implication being that the higher the plasma levels of HDL,the bigger the benefit to all individuals.Such a supposition has led to the development of "HDL therapy".It has fast become apparent however that assuming therapeutic benefits by merely raising HDL levels is highly simplistic.The most established atheroprotective function of HDL is its role in reverse cholesterol transport(RCT). However other functions of HDL not directly related to RCT may also contribute significantly to its atheioprotective properties.As well,there are many examples where the functionality of HDL changes discordantly to its concentration such that high levels of HDL can be pro-rather than antiatherogenic under certain metabolic conditions.In humans,the ability of HDL to support cholesterol efflux and maintain endothelial function,or antioxidant function can be diminished despite higher HDL levels.Conversely, apoA-IMilano mutation leads to lower HDL levels,but enhances HDL functionality.We and others have recently shown that HDL also has potent anti-inflammatory actions and can also influence the immune system.The inference of these findings are that first,changes in RCT and HDL functionality are as important,if not more so,than its changes in concentration,and second,that these changes are independent of each other.Thus,"HDL therapy" must consider alterations in RCT and HDL functionality as a result of the treatment and the implications that these changes have on the overall atheroprotective effect of the treatment.     

高密度脂蛋白——重要而又尚未攻克的靶点

近年来高密度脂蛋白是抗动脉粥样硬化领域的研究热点,高密度脂蛋白通过逆胆固醇转运、抗氧化、抗炎、抗血栓、促纤溶等作用发挥着心血管保护作用,被认为是一个具有锦绣前景的干预治疗靶点。如何提高高密度脂蛋白胆固醇水平和改善高密度脂蛋白的质量与功能,使其更好的发挥心血管保护作用是研究者们关心的热点问题,多种干预高密度脂蛋白功能的新治疗措施的临床试验正在进行中,为冠心病的防治提供新的手段。     

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.     

microRNA对ABCA1调控的研究进展

microRNA(miRNA)对许多生物学过程具有微调作用,ATP结合盒转运体A1(ABCA1)是调节高密度脂蛋白(HDL)代谢和功能的关键蛋白。目前已发现多种miRNA可抑制ABCA1表达,进而抑制胆固醇流出,降低血清HDL水平。而沉默miRNA或抑制其表达则无法抑制胆固醇流出,血清HDL水平无改变。目前对miRNA调控ABCA1表达进行了大量研究,有望带来治疗技术的革新,在调节脂代谢和抗动脉粥样硬化领域具有广阔前景。     

Role of Hepatic Lipase and Endothelial Lipase in High-Density Lipoprotein—Mediated Reverse Cholesterol Transport

Reverse cholesterol transport (RCT) constitutes a key part of the atheroprotective properties of high-density lipoproteins (HDL). Hepatic lipase (HL) and endothelial lipase (EL) are negative regulators of plasma HDL cholesterol levels. Although overexpression of EL decreases overall macrophage-to-feces RCT, knockout of both HL and EL leaves RCT essentially unaffected. With respect to important individual steps of RCT, current data on the role of EL and HL in cholesterol efflux are not conclusive. Both enzymes increase hepatic selective cholesterol uptake; however, this does not translate into altered biliary cholesterol secretion, which is regarded the final step of RCT. Also, the impact of HL and EL on atherosclerosis is not clear cut; rather it depends on respective experimental conditions and chosen models. More mechanistic insights into the diverse biological properties of these enzymes are therefore required to firmly establish EL and HL as targets for the treatment of atherosclerotic cardiovascular disease.     

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。