Lewis Gary F, Rader Daniel J
Department of Medicine and Physiology, University of Toronto, Canada.
Circ Res. 2005 Jun 24;96(12):1221-32. doi: 10.1161/01.RES.0000170946.56981.5c.
The metabolism of high-density lipoproteins (HDL), which are inversely related to risk of atherosclerotic cardiovascular disease, involves a complex interplay of factors regulating HDL synthesis, intravascular remodeling, and catabolism. The individual lipid and apolipoprotein components of HDL are mostly assembled after secretion, are frequently exchanged with or transferred to other lipoproteins, are actively remodeled within the plasma compartment, and are often cleared separately from one another. HDL is believed to play a key role in the process of reverse cholesterol transport (RCT), in which it promotes the efflux of excess cholesterol from peripheral tissues and returns it to the liver for biliary excretion. This review will emphasize 3 major evolving themes regarding HDL metabolism and RCT. The first theme is that HDL is a universal plasma acceptor lipoprotein for cholesterol efflux from not only peripheral tissues but also hepatocytes, which are a major source of cholesterol efflux to HDL. Furthermore, although efflux of cholesterol from macrophages represents only a tiny fraction of overall cellular cholesterol efflux, it is the most important with regard to atherosclerosis, suggesting that it be specifically termed macrophage RCT. The second theme is the critical role that intravascular remodeling of HDL by lipid transfer factors, lipases, cell surface receptors, and non-HDL lipoproteins play in determining the ultimate metabolic fate of HDL and plasma HDL-c concentrations. The third theme is the growing appreciation that insulin resistance underlies the majority of cases of low HDL-c in humans and the mechanisms by which insulin resistance influences HDL metabolism. Progress in our understanding of HDL metabolism and macrophage reverse cholesterol transport will increase the likelihood of developing novel therapies to raise plasma HDL concentrations and promote macrophage RCT and in proving that these new therapeutic interventions prevent or cause regression of atherosclerosis in humans.
高密度脂蛋白（HDL）的代谢与动脉粥样硬化性心血管疾病风险呈负相关，涉及调节HDL合成、血管内重塑和分解代谢的多种因素之间的复杂相互作用。HDL的各个脂质和载脂蛋白成分大多在分泌后组装，经常与其他脂蛋白交换或转移，在血浆中被积极重塑，并且常常彼此分开清除。HDL被认为在逆向胆固醇转运（RCT）过程中起关键作用，在此过程中它促进外周组织中过量胆固醇的流出，并将其返回肝脏进行胆汁排泄。本综述将强调关于HDL代谢和RCT的3个主要发展主题。第一个主题是，HDL不仅是外周组织中胆固醇流出的通用血浆受体脂蛋白，也是肝细胞中胆固醇流出的通用血浆受体脂蛋白，肝细胞是HDL胆固醇流出的主要来源。此外，尽管巨噬细胞中胆固醇的流出仅占总体细胞胆固醇流出的一小部分，但就动脉粥样硬化而言它是最重要的，这表明它可被专门称为巨噬细胞RCT。第二个主题是脂质转移因子、脂肪酶、细胞表面受体和非HDL脂蛋白对HDL进行的血管内重塑在决定HDL的最终代谢命运和血浆HDL-c浓度方面所起的关键作用。第三个主题是人们越来越认识到胰岛素抵抗是人类大多数低HDL-c病例的基础，以及胰岛素抵抗影响HDL代谢的机制。我们对HDL代谢和巨噬细胞逆向胆固醇转运理解的进展将增加开发新疗法以提高血浆HDL浓度并促进巨噬细胞RCT的可能性，并增加证明这些新治疗干预措施可预防或导致人类动脉粥样硬化消退的可能性。
