Department of Atherosclerosis, Merck Research Laboratories, Rahway, NJ 07065.
J Lipid Res. 2013 Oct;54(10):2858-65. doi: 10.1194/jlr.M041541. Epub 2013 Jul 29.
Cholesteryl ester transfer protein (CETP) transfers cholesteryl ester and triglyceride between HDL and apoB-containing lipoproteins. Anacetrapib (ANA), a reversible inhibitor of CETP, raises HDL cholesterol and lowers LDL cholesterol in dyslipidemic patients. We previously demonstrated that ANA increases macrophage-to-feces reverse cholesterol transport and fecal cholesterol excretion in hamsters, and increased preβ HDL-dependent cholesterol efflux via ABCA1 in vitro. However, the effects of ANA on in vivo preβ HDL have not been characterized. In vitro, ANA inhibited the formation of preβ, however in ANA-treated dyslipidemic hamsters, preβ HDL levels (measured by two-dimensional gel electrophoresis) were increased, in contrast to in vitro findings. Because changes in plasma preβ HDL have been proposed to potentially affect markers of cholesterol absorption with other CETP inhibitors, a dual stable isotope method was used to directly measure cholesterol absorption in hamsters. ANA treatment of hamsters (on either dyslipidemic or normal diet) had no effect on cholesterol absorption, while dalcetrapib-treated hamsters displayed an increase in cholesterol absorption. Taken together, these data support the notion that ANA promotes preβ HDL functionality in vivo, with no effects on cholesterol absorption.
胆固醇酯转移蛋白（CETP）在 HDL 和载脂蛋白 B 脂蛋白之间转移胆固醇酯和甘油三酯。Anacetrapib（ANA）是 CETP 的可逆抑制剂，可提高血脂异常患者的 HDL 胆固醇并降低 LDL 胆固醇。我们之前证明，ANA 增加了仓鼠巨噬细胞向粪便的胆固醇逆向转运和粪便胆固醇排泄，并通过 ABCA1 在体外增加了前β HDL 依赖性胆固醇流出。然而，ANA 对体内前β HDL 的影响尚未得到表征。体外，ANA 抑制前β的形成，然而在 ANA 治疗的血脂异常仓鼠中，前β HDL 水平（通过二维凝胶电泳测量）增加，与体外发现相反。因为已经提出血浆前β HDL 的变化可能会影响其他 CETP 抑制剂的胆固醇吸收标志物，因此使用双稳定同位素方法直接测量仓鼠中的胆固醇吸收。ANA 处理的仓鼠（在高脂血症或正常饮食上）对胆固醇吸收没有影响，而 dalcetrapib 处理的仓鼠显示胆固醇吸收增加。总之，这些数据支持 ANA 在体内促进前β HDL 功能，而对胆固醇吸收没有影响的观点。
