失功能性HDL研究进展

高密度脂蛋白胆固醇(HDL-C)水平与动脉粥样硬化呈负相关,HDL被认为具有抗动脉粥样硬化(AS)作用。但急性期反应、慢性炎症及一些代谢性疾病中,HDL组成成分变化及其功能基团的病理性修饰可造成HDL失功能化,失功能性HDL中蛋白质、脂类、酶类发生特征性改变,具有促动脉粥样硬化作用。随着研究深入,人们逐步认识到HDL的功能比HDL-C水平更重要。microRNAs与失功能性HDL具有相关性,还参与心血管系统及代谢系统疾病的发生发展,HDL受到包括microRNAs在内的一系列信号分子调控。本文主要综述失功能性HDL的结构、特征以及与动脉粥样硬化、microRNAs之间的关系,为动脉粥样硬化防治提供新的思路和方法。     

HDL蛋白质组分临床研究新进展

高密度脂蛋白胆固醇(HDL-C)水平与冠心病风险呈负相关,低HDL-C水平增加心血管疾病风险,是心血管疾病的独立危险因素.然而升高HDL-C水平的药物治疗并没有明显的临床获益,没有起到降低心血管疾病风险的预期效果,因此高密度脂蛋白(HDL)功能比HDL-C水平更好地预测心血管事件的发生.HDL是蛋白质含量最高的脂蛋白,由于蛋白质组学技术的进步,越来越多的HDL蛋白质成分被发现,除了传统的载脂蛋白、酶类,还包括脂质转移蛋白、急性期反应蛋白、补体成分、蛋白酶抑制剂,HDL的功能也从脂质转运扩展到感染免疫、急性期反应、补体激活、离子结合等,不仅参与动脉粥样硬化的发生发展,在终末期肾病、糖尿病等高心血管风险疾病中也发挥重要作用.本文就HDL蛋白质成分、功能及在冠心病和高心血管风险疾病中的作用做一综述.     

HDL亚类和功能的研究进展

高密度脂蛋白(HDL)是一种高度异质型脂蛋白,具有抗动脉粥样硬化(AS)作用。HDL因其密度、颗粒大小、电荷和组成成分不同,可分为不同的亚类,且功能各异。近年来研究发现,在糖尿病、冠心病等疾病情况下,HDL结构和功能发生改变,成为失功能性HDL,具有导致动脉粥样硬化的作用。本文就HDL的亚类、HDL的功能和失功能性HDL进行综述。     

In vivo effects of anacetrapib on preβ HDL: improvement in HDL remodeling without effects on cholesterol absorption

Cholesteryl ester transfer protein (CETP) transfers cholesteryl ester and triglyceride between HDL and apoB-containing lipoproteins. Anacetrapib (ANA), a reversible inhibitor of CETP, raises HDL cholesterol and lowers LDL cholesterol in dyslipidemic patients. We previously demonstrated that ANA increases macrophage-to-feces reverse cholesterol transport and fecal cholesterol excretion in hamsters, and increased preβ HDL-dependent cholesterol efflux via ABCA1 in vitro. However, the effects of ANA on in vivo preβ HDL have not been characterized. In vitro, ANA inhibited the formation of preβ, however in ANA-treated dyslipidemic hamsters, preβ HDL levels (measured by two-dimensional gel electrophoresis) were increased, in contrast to in vitro findings. Because changes in plasma preβ HDL have been proposed to potentially affect markers of cholesterol absorption with other CETP inhibitors, a dual stable isotope method was used to directly measure cholesterol absorption in hamsters. ANA treatment of hamsters (on either dyslipidemic or normal diet) had no effect on cholesterol absorption, while dalcetrapib-treated hamsters displayed an increase in cholesterol absorption. Taken together, these data support the notion that ANA promotes preβ HDL functionality in vivo, with no effects on cholesterol absorption.     

HDL能抵抗内毒素引起得小鼠损伤

目的:观察HDL、LPS和(HDL+LPS)对小鼠血液SOD及MDA的影响,研究HDL抗LPS的作用.方法:(1)用不同浓度的PEG-6000离心人血浆脂蛋白,提取HDL并脱脂;(2)给小鼠注射HDL,LPS或HDL+LPS,对照组小鼠注射生理盐水;观察小鼠存活时间,测定其血液中SOD活性及MDA含量.结果:(1)相比对照组及HDL组,LPS组和HDL+LPS组小鼠的存活时间明显缩短,且后两者之间存在显著性差异;(2)LPS组小鼠血浆中SOD活性降低,MDA含量升高,均和其他三组有显著性差异.结论:LPS能使内毒素损伤小鼠血浆中SOD活性降低,MDA含量升高,HDL有抗内毒素损伤的作用.     

HDL and cholesterol: life after the divorce?

For decades, HDL and HDL-cholesterol (HDL-C) levels were viewed as synonymous, and modulation of HDL-C levels by drug therapy held great promise for the prevention and treatment of cardiovascular disease. Nevertheless, recent failures of drugs that raise HDL-C to reduce cardiovascular risk and the now greater understanding of the complexity of HDL composition and biology have prompted researchers in the field to redefine HDL. As such, the focus of HDL has now started to shift away from a cholesterol-centric view toward HDL particle number, subclasses, and other alternative metrics of HDL. Many of the recently discovered functions of HDL are, in fact, not strictly conferred by its ability to promote cholesterol flux but by the other molecules it transports, including a diverse set of proteins, small RNAs, hormones, carotenoids, vitamins, and bioactive lipids. Based on HDL''s ability to interact with almost all cells and transport and deliver fat-soluble cargo, HDL has the remarkable capacity to affect a wide variety of endocrine-like systems. In this review, we characterize HDL''s unique cargo and address the functional relevance and consequences of HDL transport and delivery of noncholesterol molecules to recipient cells and tissues.     

人动脉平滑肌细胞HDL受体酶联测定法

利用辣根过氧化物酶（HRP）与纯化的高密度脂蛋白（HDL）交联,并将人动脉平滑肌细胞（SMC）固定于酶标板上,成功地建立了人动脉平滑肌细胞HDL受体的酶联测定法．1材料与方法1．1材料辣根过氧化物酶（HRP,RZ=3.0,Sigma）;96孔酶标板（Sigma）;培养基DMEM（GIBCO）．1．2人动脉平滑肌细胞培养培养按本室汪浩川[1]方法体外培养．1．3去apoE-HDL3制备人血清去apoE-HDL3（d=1.20～1.175）按改进的磷钨酸钠-氯化镁沉淀密度梯度超速离心法制备[2]．然后按张林华等[3]一次性密度梯度超速离心分离法分离HDL．SDS-PAGE电泳鉴…     

载脂蛋白AI对HDL生成影响的研究新进展

载脂蛋白AI(apolipoprotein A-I,apoA-I)是高密度脂蛋白(high-density lipoprotein,HDL)的主要蛋白成分,其中两性α-螺旋是apoA-I相应功能的结构基础。ApoA-I分子N-端是动态的四螺旋束结构,C-端形成无规则的螺旋结构,是介导蛋白质与磷脂结合的功能域。两分子apoA-I呈反向平行的双带结构环绕磷脂双分子层形成圆盘状HDL,而球状HDL表面的apoA-I分子则形成三叶草结构。ATP结合盒转运蛋白A1(ATP-binding cassette transporter A1,ABCA1)介导apoA-I与磷脂及胆固醇相互作用形成新生HDL,参与胆固醇的逆向转运过程。ApoA-I、HDL作为抗动脉粥样硬化的主要作用靶标,深入了解其分子结构与功能、构象变化和相互作用及其影响脂质代谢平衡的机制对抗动脉粥样硬化药物的研发及其应用具有重要意义。     

氧化修饰HDL刺激培养人主动脉平滑肌细胞增殖

平滑肌细胞（ｓｍｏｏｔｈ ｍｕｓｃｌｅ ｃｅｌｌ,ＳＭＣ）增殖在动脉粥样硬化（ａｔｈｅｒｏｓｃｌｅｒｏｓｉｓ,ＡＳ）形成中起着重要作用。氧化修饰ＨＤＬ（ｏｘｉｄｉｘｅｄ ＨＤＬ,ＯＸ－ＨＤＬ）可刺激＾３Ｈ－ＴｄＲ掺入培养人动脉ＳＭＣ的ＤＮＡ,促进ＳＭＣ增殖。以四甲工偶氮唑盐９ＭＴＴ）法直接观察ＯＸ－ＨＤＬ对培养人动脉ＳＭＣ增殖细胞数的影响。结果显示,天然ＨＤＬ（ｎａｔｉｖｅ ＨＤＬ Ｎ－ＨＤＬ）对     

氧化HDL2在大肠肝窦状隙细胞内代谢

大鼠肝窦状隙细胞培养结果显示：氧化高密度脂蛋白２对异硫氰酸荧光素荧光标记ｏｘ－ＨＤＬ２的细胞结合有竞争抑制作用,而ＨＤＬ２则无。细胞内ＦＩＴＣ－ｏｘ－ＨＤＬ２的荧光强度和「＾３Ｈ『ＣＥ－ｏｘ－ＨＤＬ２的的４５．５％和ｒＨＤＬ２的６１．４％。内吞ＦＳ主要存在于三氯醋酸沉淀部分,而放射强度主要存在于ＴＣＡ上清液部分。     

氧化修饰HDL剌激培养人主动脉平滑肌细胞增殖

平滑肌细胞（smooth muscle cell, SMC）增殖在动脉粥样硬化（atherosclerosis, AS）形成中起着重要作用.氧化修饰HDL（oxidized HDL, OX-HDL）可刺激 ³H-TdR掺入培养人动脉SMC的DNA,促进SMC增殖.以四甲基偶氮唑盐(MTT)法直接观察OX-HDL对培养人动脉SMC增殖细胞数的影响.结果显示,天然HDL（native HDL N-HDL）对SMC增殖没有影响,而OX-HDL则显著刺激SMC增殖（P＜0.01）,N-HDL显著抑制OX-LDL刺激SMC增殖作用（P＜0.01）,而OX-HDL则显著增加OX-LDL刺激SMC增殖作用（P＜0.01）     

胆固醇酶试剂测定血清HDL—C的探讨

血清低密度脂蛋白(LDL)是引起动脉粥样硬化的主要致病物质,血清HDL的作用则恰恰相反,是从动脉壁上清除LDL的物质基础,可被视为防御和保护动脉血管壁的重要物质。 许多研究证明冠心病患者即使血清总胆固醇正常,而HDL亦可降低。有人认为血清HDL的降低是临床冠心病的先兆,因此,测定血清HDL更为必要。     

The HDL hypothesis: does high-density lipoprotein protect from atherosclerosis?

There is unequivocal evidence of an inverse association between plasma high-density lipoprotein (HDL) cholesterol concentrations and the risk of cardiovascular disease, a finding that has led to the hypothesis that HDL protects from atherosclerosis. This review details the experimental evidence for this “HDL hypothesis”. In vitro studies suggest that HDL has a wide range of anti-atherogenic properties but validation of these functions in humans is absent to date. A significant number of animal studies and clinical trials support an atheroprotective role for HDL; however, most of these findings were obtained in the context of marked changes in other plasma lipids. Finally, genetic studies in humans have not provided convincing evidence that HDL genes modulate cardiovascular risk. Thus, despite a wealth of information on this intriguing lipoprotein, future research remains essential to prove the HDL hypothesis correct.     

氧化修饰使HDL促动脉平滑肌细胞胆固醇流出减少

为了研究氧化修饰对高密度脂蛋白（ＨＤＬ）转运细胞胆固醇地＾３Ｈ－胆固醇负荷的培养人动脉平滑肌细胞（ＳＭＣ）分别与天然ＨＤＬ及Ｃｕ＾２＋ａｋｇ ＨＯＣｌ氧化修饰的ＨＤＬ在３７℃温育不同时间后,分别测定细胞＾３Ｈ－胆固醇清除率。结果发现,温育２４ｈ后,经Ｃｕ＾２＋或ＨＯＬｌ氧修饰后的ＨＤＬ其细胞胆因醇清除率分别较天然ＨＤＬ下降了３０．０％和４３．１％（ｐ〈０．０１）。结果还发现,Ｃｕ＾２＋或ＨＯＣｌ氧     

HDL转运的miR-223调控内皮细胞ICAM-1的表达

<正>众所周知,血浆中高密度脂蛋白HDL的浓度与心血管疾病发生的风险负相关。对HDL心血管保护功能研究最多的是它在胆固醇逆向转运中的作用。此外,HDL还有抑制多种细胞免疫炎症的作用,比如HDL可以抑制内皮细胞的激活和粘附分子的表达。HDL具有异质性,由若干结构和功能各异的颗粒亚群组成,成分复杂,包括脂蛋白、磷脂、小RNA(miR)等。这导致目前关于HDL心血管保护作用的机制了解不是很多。本文作者研究了HDL的各个组分对于内皮细胞基因表达谱和miR