氧化修饰高密度脂蛋白的研究进展

血浆高密度脂蛋白(HDL)与低密度脂蛋白(LDL)一样可以在体内外发生氧化修饰,引起其理化性质发生一系列的改变,如多不饱和脂肪酸过氧化,卵磷脂水解,蛋白质发生聚合或分解等.活体内HDL可能在动脉壁巨噬细胞、内皮细胞及中性粒细胞、单核细胞的作用下发生氧化修饰.氧化修饰HDL可能通过清道夫受体途径代谢.氧化修饰HDL产生多种致动脉粥样硬化作用.维生素E、C的摄入可能有助于防止脂蛋白的氧化.     

人血浆HDL对动脉粥样硬化家兔肝细胞膜LDL受体活性影响的研究

高胆固醇饲料喂养造成的动脉粥样硬化(As)模型家兔通过静脉注射人血浆HDL制剂,观察HDL对As家兔肝细胞膜LDL受体活性的影响.结果发现,摄取高胆固醇饲料的As家兔,其肝细胞膜LDL受体K_d值虽无明显变化但B_max值显著减小（P＜0.01,与正常对照组比较);注射HDL制剂后,As家兔肝细胞膜LDL受体K_d值仍无明显改变,但B_max值却显著回升（P＜0.01,与高脂组比较).表明人血浆HDL具有增加As家兔肝细胞膜LDL受体活性的作用.     

人血浆HDL对动脉粥样硬化家兔肝细胞膜 LDL受体活性影响的研究

高胆固醇饲料喂养造成的动脉粥样硬化（Ａｓ） 模型家兔通过静脉注射人血浆ＨＤＬ 制剂, 观察ＨＤＬ 对Ａｓ家兔肝细胞膜ＬＤＬ受体活性的影响． 结果发现, 摄取高胆固醇饲料的Ａｓ 家兔, 其肝细胞膜ＬＤＬ 受体 Ｋｄ 值虽无明显变化但Ｂｍａｘ 值显著减小（ Ｐ＜ ０－０１ , 与正常对照组比较） ; 注射ＨＤＬ 制剂后, Ａｓ 家兔肝细胞膜ＬＤＬ受体Ｋｄ 值仍无明显改变, 但Ｂｍａｘ 值却显著回升（ Ｐ＜ ０－０１ , 与高脂组比较） ． 表明人血浆ＨＤＬ 具有增加Ａｓ 家兔肝细胞膜ＬＤＬ 受体活性的作用．     

载脂蛋白A-I抗动脉粥样硬化的研究进展

载脂蛋白A—I是HDL最主要的结构成分,是卵磷脂胆固醇酰基转移酶的主要激活剂。它决定了HDL的代谢和在血浆中的浓度。实验已经证明,载脂蛋白A—I具有抗动脉粥样硬化症的功能。在这里阐述了载脂蛋白A—I的结构和制备;载脂蛋白A—I和HDL的关系以及它在抗动脉粥样硬化方面的作用和可能的机理：胆固醇的逆向转运、抗氧化作用和调节炎症反应。     

高密度脂蛋白受体(SR-BI)和胆固醇逆转运

近十几年来对小鼠的B类I型清道夫受体(SRBI)的研究,发现它是一种高亲和力的高密度脂蛋白受体,主要在肝脏和类固醇源性组织中表达。该受体能介导胆固醇酯的选择性吸收,在高密度脂蛋白(HDL)的代谢和胆固醇的“逆转运”中起重要作用。动物实验证明SRBI的表达可减少动脉粥样硬化的发生。如果SRBI对人有相似的作用,它将成为一个好的作用靶点用于临床心脑血管疾病的治疗 。     

急性期应答与胆固醇逆向转运

胆固醇逆向转运(reverse cholesterol transport,RCT)是促进外周胆固醇从细胞内流出,然后转运到肝脏进行代谢的过程,是机体抗动脉粥样硬化相关疾病的重要机制。研究表明,感染、炎症及创伤等诱导的急性期应答(acute phase response,APR)影响高密度脂蛋白的结构和功能,抑制细胞内胆固醇流出、血浆胆固醇转运及肝脏胆固醇代谢和排泌等环节,因此抑制体内RCT。APR短期抑制RCT有利于机体抗感染和组织损伤,然而,APR对RCT的进一步抑制将促进外周组织胆固醇蓄积及代谢紊乱,可能是多种感染免疫性疾病、代谢性疾病与动脉粥样硬化呈正相关的关键因素。本文就APR调节机体RCT的最新研究进展作一综述。     

apoA-Ⅰ的α螺旋在胆固醇流出中的作用

血浆载脂蛋白A-Ⅰ(apoA-Ⅰ)的水平与动脉粥样硬化(atherosclerosis,AS)性心血管疾病的风险呈负相关.ApoA-Ⅰ经载脂形成高密度脂蛋白(HDL),HDL通过促进胆固醇逆向转运(RCT),使细胞内的多余胆固醇流出.α螺旋是apoA-Ⅰ载脂的主要结构,在apoA-Ⅰ参与的胆固醇流出中具有重要作用.模拟α螺旋建立的apoA-Ⅰ模拟肽能通过不同方式发挥抗AS的作用.本文就α螺旋在胆固醇流出中的作用作一综述,以便进一步探索apoA-Ⅰ的结构对胆固醇流出的影响,为以apoA-Ⅰ为靶点防治AS提供理论基础.     

高密度脂蛋白抗动脉粥样硬化的新机制：调节干/祖细胞的功能

高密度脂蛋白（high density lipoprotein,HDL）血浆水平与动脉粥样硬化（atherosclerosis,AS）性心血管疾病呈负相关,成为抗AS的重要靶点和热点.然而,近年来多个临床试验未能证明升高血浆HDL的水平对心血管的保护作用,使得人们开始重新审视HDL抗AS功能生物学特性的复杂性.近5年来的研究发现,HDL可通过对造血干细胞（hematopoietic stem cells,HSCs）和内皮祖细胞（endothelial progenitor cells,EPCs）功能的调节发挥抗AS 的作用,本文就这一新机制进行综述,期待为HDL迄今尚不完全清楚的复杂心血管保护机制提供研究思路.     

高密度脂蛋白胆固醇水平相关的遗传学研究最新进展

研究已经证实血浆高密度脂蛋白胆固醇(HDL-C)水平与冠状动脉疾病(CAD)的发生呈负相关,因此,HDL-C水平的调控成为CAD治疗的研究热点.HDL水平高低与其自身的产生和代谢密切相关,而HDL的产生和代谢主要由相应的调控基因决定,有研究表明,血浆HDL-C水平具有显著的遗传基础,遗传率达到40%～60%,提示研究影响HDL-C水平的遗传性因素具有重要意义.候选基因、全基因组连锁以及近来的全基因组关联(GWA)研究已鉴定出影响血浆HDL-C水平的多种遗传变异,但这些遗传变异并不都与CAD相关,对于其功能性作用还未阐明.本文将分别对HDL的结构、产生和代谢,以及HDL-C水平相关的遗传性因素进行总结,并着重结合候选基因分析以及近来GWA研究的遗传学发现,阐述造成HDL-C水平变化的重要因子.提示运用综合性方法研究影响HDL-C水平的遗传性因素对于阐明HDL-C与CAD的关系,揭示CAD治疗新途径具有重要意义.     

载脂蛋白A-Ⅰ抗动脉粥样硬化的研究进展

载脂蛋白A-是HDL最主要的结构成分,是卵磷脂胆固醇酰基转移酶的主要激活剂。它决定了HDL的代谢和在血浆中的浓度。实验已经证明,载脂蛋白A-Ⅰ具有抗动脉粥样硬化症的功能。在这里阐述了载脂蛋白A-Ⅰ的结构和制备;载脂蛋白A-Ⅰ和HDL的关系以及它在抗动脉粥样硬化方面的作用和可能的机理：胆固醇的逆向转运、抗氧化作用和调节炎症反应。     

Lipoprotein lipase-facilitated uptake of LDL is mediated by the LDL receptor

LPL mediates the uptake of lipoproteins into different cell types independent of its catalytic activity. The mechanism of this process and its physiological relevance are not clear. Taking into account the importance of the endothelial barrier for lipoprotein uptake, in vitro studies with primary aortic endothelial cells from wild-type and low density lipoprotein receptor (LDLR)-deficient (LDLR(-/-)) mice were performed. Addition of LPL almost doubled the uptake of LDL into wild-type cells. However, there was virtually no LPL-mediated change of LDL uptake into LDLR(-/-) cells. Upregulation of LDLR by lipoprotein-deficient serum/lovastatin in wild-type cells resulted in a 7-fold increase of LPL-mediated LDL uptake. Uptake of chylomicron remnants was not affected by LDLR expression. In proteoglycan-deficient cells, LPL did not increase the uptake of lipoproteins. The physiological relevance of this pathway was studied in mice that were both LDLR(-/-) and transgenic for catalytically inactive LPL in muscle. In the presence of LDLR, inactive LPL reduced LDL cholesterol significantly (13-24%). In the absence of LDLR, LDL cholesterol was not affected by transgenic LPL. Metabolic studies showed that in the presence of LDLR, LPL increased the muscular uptake of LDL by 77%. In the absence of LDLR, transgenic LPL did not augment LDL uptake. Chylomicron uptake was not affected by the LDLR genotype. We conclude that LPL-mediated cellular uptake of LDL, but not of chylomicrons, is dependent on the presence of both LDLR and proteoglycans.     

The effects of ABCG5/G8 polymorphisms on plasma HDL cholesterol concentrations depend on smoking habit in the Boston Puerto Rican Health Study

Low HDL-cholesterol (HDL-C) is associated with an increased risk for atherosclerosis, and concentrations are modulated by genetic factors and environmental factors such as smoking. Our objective was to assess whether the association of common single-nucleotide polymorphisms (SNPs) at ABCG5/G8 (i18429G>A, i7892T>C, Gln604GluC>G, 5U145A>C, Tyr54CysA>G, Asp19HisG>C, i14222A>G, and Thr400LysC>A) genes with HDL-C differs according to smoking habit. ABCG5/G8 SNPs were genotyped in 845 participants (243 men and 602 women). ABCG5/G8 (i7892T>C, 5U145A>C, Tyr54CysA>G, Thr400LysC>A) SNPs were significantly associated with HDL-C concentrations (P < 0.001–0.013) by which carriers of the minor alleles at the aforementioned polymorphisms and homozygotes for the Thr400 allele displayed lower HDL-C. A significant gene-smoking interaction was found, in which carriers of the minor alleles at ABCG5/G8 (Gln604GluC>G, Asp19HisG>C, i14222A>G) SNPs displayed lower concentrations of HDL-C only if they were smokers (P = 0.001–0.025). Also, for ABCG8_Thr400LysC>A SNP, smokers, but not nonsmokers, homozygous for the Thr400 allele displayed lower HDL-C (P = 0.004). Further analyses supported a significant haplotype global effect on lowering HDL-C (P = 0.002) among smokers. In conclusion, ABCG5/G8 genetic variants modulate HDL-C concentrations, leading to an HDL-C-lowering effect and thereby a potential increased risk for atherosclerosis only in smokers.     

Genetic analysis of murine strains C57BL/6J and C3H/HeJ to confirm the map position ofAth-1, a gene determining atherosclerosis susceptibility

Previous results suggested that strains C57BL/6J and C3H/HeJ differed in a single gene for atherosclerosis susceptibility, calledAth-1. Based on data from recombinant inbred strainsAth-1 was tentatively assigned to chromosome 1 linked toAlp-2. In this report, a cross between C57BL/6 and C3H/HeJ was carried out in order to test whether the tentative map position was correct. Parental strains and F₁ and F₂ progeny were examined. Susceptible alleles ofAth-1, found in C57BL/6, are associated with relatively low levels of high-density lipoprotein (HDL)-cholesterol in animals fed an atherogenic diet; resistant alleles ofAth-1 are associated with relatively high levels of HDL-cholesterol. F₁ progeny have HDL levels that are intermediate between these of the two parental strains. Among the F₂ progeny,Alp-2 andAth-1 cosegregated, providing confirmatory evidence thatAth-1 is linked toAlp-2 on chromosome 1. Three mice recombinant forAlp-2 andAth-1 were found among the 60 chromosomes tested, giving an estimated map distance between these two genes of 5.0±2.8 (SE) cM. The phenotypic characteristics ofAth-1 resemble a genetic trait in humans, hyperalphalipoproteinemia, which is characterized by elevated levels of HDL-cholesterol, reduced risk of heart disease, and increased longevity.This work was supported by Grant HL-32087 from the Heart, Lung, and Blood Institute, National Institutes of Health, Grant 1858 from the Council for Tobacco Research, Grant 86-1387 from the American Heart Association with funds contributed in part by the Alameda, Orange, and Santa Barbara County Chapters, and Grants 85-N132A and 85-N136A from the California Affiliate of the American Heart Association.     

Oxidized lipoprotein lipids and atherosclerosis

Plasma lipoproteins contain variable amounts of lipid oxidation products (LOP), which are known to impair normal physiological functions and stimulate atherosclerotic processes. Recent evidence indicates that plasma lipoproteins are active carriers of LOP, low-density lipoprotein (LDL) directing transport toward peripheral tissues, and high-density lipoprotein (HDL) being active in the reverse transport. It has been proposed that the lipoprotein-specific transport of LOP could play a role in atherosclerosis-related effects of LDL and HDL. This article gives an overview of the present knowledge of lipoprotein LOP transport and its association with the risk of atherosclerosis and cardiovascular diseases (CVD). Evidence of the significance of lipoprotein LOP transport comes mainly from studies of physiological oxidative stress and is supported by studies of the functionality apolipoprotein A-1 mimetic peptides. A large body of data has accumulated indicating that lipoprotein LOP transport is connected to the risk of atherosclerosis. While high levels of LOP carried by LDL are indicative of elevated risk, high LOP level in HDL appears to associate with protection. If confirmed, the proposed lipoprotein LOP transport function would affect conception of the etiology of atherosclerosis, but would not conflict current views of the pathophysiological mechanisms. It could open new perspectives, such as the dietary origin of LOP, and the protective function of HDL in clearance of LOP. Focusing on LOP could give additional tools especially for prevention and diagnosis, but would not radically change the management of atherosclerosis and CVD.     

ApoA-I cleaved by transthyretin has reduced ability to promote cholesterol efflux and increased amyloidogenicity

A fraction of plasma transthyretin (TTR) circulates in HDL through binding to apolipoprotein A-I (apoA-I). Moreover, TTR is able to cleave the C terminus of lipid-free apoA-I. In this study, we addressed the relevance of apoA-I cleavage by TTR in lipoprotein metabolism and in the formation of apoA-I amyloid fibrils. We determined that TTR may also cleave lipidated apoA-I, with cleavage being more effective in the lipid-poor prebeta-HDL subpopulation. Upon TTR cleavage, discoidal HDL particles displayed a reduced capacity to promote cholesterol efflux from cholesterol-loaded THP-1 macrophages. In similar assays, TTR-containing HDL from mice expressing human TTR in a TTR knockout background had a decreased ability to perform reverse cholesterol transport compared with similar particles from TTR knockout mice, reinforcing the notion that cleavage by TTR reduces the ability of apoA-I to promote cholesterol efflux. As amyloid deposits composed of N-terminal apoA-I fragments are common in the atherosclerotic intima, we assessed the impact of TTR cleavage on apoA-I aggregation and fibrillar growth. We determined that TTR-cleaved apoA-I has a high propensity to form aggregated particles and that it formed fibrils faster than full-length apoA-I, as assessed by electron microscopy. Our results show that apoA-I cleavage by TTR may affect HDL biology and the development of atherosclerosis by reducing cholesterol efflux and increasing the apoA-I amyloidogenic potential.