Department of Endocrinology, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands.
Cardiovasc Ther. 2011 Dec;29(6):e89-99. doi: 10.1111/j.1755-5922.2010.00201.x. Epub 2010 Jul 14.
As delineated in this review, cholesteryl ester transfer protein (CETP) contributes to an atherogenic lipoprotein profile by redistributing cholesteryl esters from high density lipoprotein (HDL) toward apolipoprotein B-containing lipoproteins, especially when the concentration of acceptor triglyceride-rich lipoproteins is elevated. However, this lipid transfer protein may have antiatherogenic proprerties as well. Experimental evidence is accumulating which suggests that the atheroprotective reverse cholesterol transport pathway, whereby cholesterol is removed from peripheral macrophages to the liver for metabolism and biliary excretion, is stimulated by CETP in vivo. CETP could also play a role in host defense against infection and inflammatory processes. Moreover, recently published observational studies show that higher CETP levels may confer cardiovascular protection, whereas reported associations of cardiovascular disease (CVD) with CETP gene variations are equivocal. The concept that HDL cholesterol raising through inhibition of CETP may ameliorate CVD risk has been challenged by the failure of the CETP inhibitor, torcetrapib. Adverse clinical outcome associated with the use of this CETP inhibitor has been attributed to off-target effects, which relate to stimulation of aldosterone. Other CETP inhibitors, such as dalcetrapib and anacetrapib, are unlikely to increase blood pressure. Dalcetrapib is less potent than anacetrapib, which doubles HDL cholesterol. Both inhibitors considerably lower LDL cholesterol.Serious concerns remain about the validity of the concept that HDL cholesterol raising by means of CETP inhibition is a viable strategy. Results of ongoing clinical trials with these drugs will have to be awaited before making up the balance between possible benefits and harms related to pharmacological CETP inhibition.
如本文所述，胆固醇酯转移蛋白（CETP）通过将胆固醇酯从高密度脂蛋白（HDL）重新分配到载脂蛋白 B 含量丰富的脂蛋白中，特别是当接受者富含甘油三酯的脂蛋白浓度升高时，有助于形成致动脉粥样硬化的脂蛋白谱。然而，这种脂质转移蛋白也可能具有抗动脉粥样硬化特性。越来越多的实验证据表明，CETP 在体内刺激了胆固醇从外周巨噬细胞转移到肝脏进行代谢和胆汁排泄的抗动脉粥样硬化的逆向胆固醇转运途径。CETP 还可能在宿主对感染和炎症过程的防御中发挥作用。此外，最近发表的观察性研究表明，CETP 水平升高可能对心血管有保护作用，而报告的与 CETP 基因突变相关的心血管疾病（CVD）相关性存在争议。通过抑制 CETP 升高 HDL 胆固醇可能改善 CVD 风险的概念受到了 CETP 抑制剂 torcetrapib 失败的挑战。与使用这种 CETP 抑制剂相关的不良临床结果归因于脱靶效应，这与醛固酮的刺激有关。其他 CETP 抑制剂，如 dalcetrapib 和 anacetrapib，不太可能增加血压。dalcetrapib 的效力低于 anacetrapib，后者可使 HDL 胆固醇增加一倍。这两种抑制剂均可显著降低 LDL 胆固醇。关于通过抑制 CETP 升高 HDL 胆固醇是否是一种可行策略的概念仍然存在严重的担忧。这些药物的正在进行的临床试验的结果将不得不等待，然后才能在与药理学 CETP 抑制相关的可能益处和危害之间取得平衡。
