Aggregation and fusion of low-density lipoproteins in vivo and in vitro.
Aggregation and fusion of low-density lipoproteins in vivo and in vitro.
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DOI：
10.1515/bmc-2013-0016
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发表时间：
2013-10
影响因子：
--
通讯作者：
Gursky O
中科院分区：
文献类型：
--
作者：
Lu M;Gursky O
低密度脂蛋白，又称“坏胆固醇”，是循环中胆固醇的主要载体，也是动脉粥样硬化的主要危险因素。血浆低密度脂蛋白是20到25纳米的纳米颗粒，含有胆固醇酯核心，周围环绕着磷脂单分子层和单一拷贝的载脂蛋白B(550 KDa)。动脉粥样硬化的早期迹象是低密度脂蛋白衍生的脂滴在动脉壁中积聚。根据被广泛接受的“保留反应假说”，低密度脂蛋白与动脉内膜中的细胞外基质蛋白多糖结合，引起水解性和氧化性修饰，从而促进低密度脂蛋白的聚集和融合。这增强了动脉巨噬细胞对低密度脂蛋白的摄取，并触发了一系列致病反应，最终导致动脉粥样硬化病变的发展。因此，低密度脂蛋白的聚集、融合和脂滴的形成是动脉粥样硬化形成的重要早期步骤。在体外，各种对低密度脂蛋白的酶和非酶修饰可以诱导这些反应，从而为其详细分析提供有用的模型。在这里，我们总结了导致低密度脂蛋白聚集、融合和脂滴形成的体内和体外修饰的最新知识；概述了用于研究这些反应的技术；并提出了这些促动脉粥样硬化过程的分子机制。这些知识对于识别能够促进或阻止体内低密度脂蛋白聚集和融合的内源性和外源性因素以及帮助建立新的潜在治疗靶点以减缓甚至阻止这些致病反应是必不可少的。
Low-density lipoproteins (LDLs, also known as ‘bad cholesterol’) are the major carriers of circulating cholesterol and the main causative risk factor of atherosclerosis. Plasma LDLs are 20- to 25-nm nanoparticles containing a core of cholesterol esters surrounded by a phospholipid monolayer and a single copy of apolipoprotein B (550 kDa). An early sign of atherosclerosis is the accumulation of LDL-derived lipid droplets in the arterial wall. According to the widely accepted ‘response-to-retention hypothesis’, LDL binding to the extracellular matrix proteoglycans in the arterial intima induces hydrolytic and oxidative modifications that promote LDL aggregation and fusion. This enhances LDL uptake by the arterial macrophages and triggers a cascade of pathogenic responses that culminate in the development of atherosclerotic lesions. Hence, LDL aggregation, fusion, and lipid droplet formation are important early steps in atherogenesis. In vitro, a variety of enzymatic and nonenzymatic modifications of LDL can induce these reactions and thereby provide useful models for their detailed analysis. Here, we summarize current knowledge of the in vivo and in vitro modifications of LDLs leading to their aggregation, fusion, and lipid droplet formation; outline the techniques used to study these reactions; and propose a molecular mechanism that underlies these pro-atherogenic processes. Such knowledge is essential in identifying endogenous and exogenous factors that can promote or prevent LDL aggregation and fusion in vivo and to help establish new potential therapeutic targets to decelerate or even block these pathogenic reactions.