Kleber M E, Grammer T B, März W
LURIC Study gGmBH, Freiburgim Breisgau.
MMW Fortschr Med. 2010 Jul 1;152 Suppl 2:47-55.
Large epidemiological studies have consistently shown that plasma levels of high-density lipoprotein (HDL) correlate inversely with cardiovascular risk. The apparent cardioprotective role of HDL has primarily been attributed to its participation in reverse cholesterol transport (RCT) but there is also substantial evidence that supports the concept of HDL and apoA-I preventing oxidative damage, inhibiting systemic inflammation, promoting vascular integrity and preventing thrombosis. Besides conventional therapy to increase HDL like physical exercise, weight loss and dietary changes new strategies to intervene at various steps of its metabolism have been proposed and are in development. One of the most promising approaches is inhibiting cholesteryl ester transfer protein (CETP)which plays a central role in RCT by transferring cholesteryl esters from HDL to apoB containing lipoproteins in exchange for triglycerides. The failure of the CETP inhibitor torcetrapib, however, to cause any benefit on cardiovascular outcomes despite significantly increased HDL levels in several clinical trials casted doubts upon the concept of CETP inhibition. Meanwhile, off target toxicity could be shown for torcetrapib and a new generation of CETP inhibitors stands ready to be tested in large clinical trials. This article describes the formation and remodeling of HDL, how HDL is thought to be beneficial for the vasculature and what options we have today to increase HDL levels with a special focus on CETP inhibition.
大型流行病学研究一致表明,血浆高密度脂蛋白(HDL)水平与心血管风险呈负相关。HDL明显的心脏保护作用主要归因于其参与逆向胆固醇转运(RCT),但也有大量证据支持HDL和载脂蛋白A-I预防氧化损伤、抑制全身炎症、促进血管完整性和预防血栓形成的概念。除了通过体育锻炼、减肥和饮食改变等传统疗法来提高HDL水平外,人们还提出并正在开发在其代谢的各个步骤进行干预的新策略。最有前景的方法之一是抑制胆固醇酯转运蛋白(CETP),该蛋白在RCT中起着核心作用,它将胆固醇酯从HDL转移到含载脂蛋白B的脂蛋白中,以交换甘油三酯。然而,在几项临床试验中,尽管CETP抑制剂托彻普贝显著提高了HDL水平,但并未给心血管结局带来任何益处,这使人们对CETP抑制的概念产生了怀疑。与此同时,托彻普贝可能存在脱靶毒性,新一代CETP抑制剂已准备好在大型临床试验中进行测试。本文描述了HDL的形成和重塑、HDL被认为对脉管系统有益的方式以及我们目前提高HDL水平的选择,特别关注CETP抑制。