Millar John S, Lassman Michael E, Thomas Tiffany, Ramakrishnan Rajasekhar, Jumes Patricia, Dunbar Richard L, deGoma Emil M, Baer Amanda L, Karmally Wahida, Donovan Daniel S, Rafeek Hashmi, Wagner John A, Holleran Stephen, Obunike Joseph, Liu Yang, Aoujil Soumia, Standiford Taylor, Gutstein David E, Ginsberg Henry N, Rader Daniel J, Reyes-Soffer Gissette
University of Pennsylvania, Philadelphia, PA 19104
Merck & Co., Inc., Kenilworth, NJ 07033.
J Lipid Res. 2017 Jun;58(6):1214-1220. doi: 10.1194/jlr.M074880. Epub 2017 Mar 17.
Cholesteryl ester transfer protein (CETP) mediates the transfer of HDL cholesteryl esters for triglyceride (TG) in VLDL/LDL. CETP inhibition, with anacetrapib, increases HDL-cholesterol, reduces LDL-cholesterol, and lowers TG levels. This study describes the mechanisms responsible for TG lowering by examining the kinetics of VLDL-TG, apoC-II, apoC-III, and apoE. Mildly hypercholesterolemic subjects were randomized to either placebo (N = 10) or atorvastatin 20 mg/qd (N = 29) for 4 weeks (period 1) followed by 8 weeks of anacetrapib, 100 mg/qd (period 2). Following each period, subjects underwent stable isotope metabolic studies to determine the fractional catabolic rates (FCRs) and production rates (PRs) of VLDL-TG and plasma apoC-II, apoC-III, and apoE. Anacetrapib reduced the VLDL-TG pool on a statin background due to an increased VLDL-TG FCR (29%; = 0.002). Despite an increased VLDL-TG FCR following anacetrapib monotherapy (41%; = 0.11), the VLDL-TG pool was unchanged due to an increase in the VLDL-TG PR (39%; = 0.014). apoC-II, apoC-III, and apoE pool sizes increased following anacetrapib; however, the mechanisms responsible for these changes differed by treatment group. Anacetrapib increased the VLDL-TG FCR by enhancing the lipolytic potential of VLDL, which lowered the VLDL-TG pool on atorvastatin background. There was no change in the VLDL-TG pool in subjects treated with anacetrapib monotherapy due to an accompanying increase in the VLDL-TG PR.
胆固醇酯转运蛋白（CETP）介导高密度脂蛋白（HDL）胆固醇酯与极低密度脂蛋白（VLDL）/低密度脂蛋白（LDL）中的甘油三酯（TG）进行交换。使用阿那曲泊帕抑制CETP可升高HDL胆固醇水平，降低LDL胆固醇水平，并降低TG水平。本研究通过检测VLDL-TG、载脂蛋白C-II（apoC-II）、载脂蛋白C-III（apoC-III）和载脂蛋白E（apoE）的动力学，描述了导致TG降低的机制。轻度高胆固醇血症受试者被随机分为安慰剂组（N = 10）或阿托伐他汀20 mg/每日组（N = 29），为期4周（第1阶段），随后接受8周的阿那曲泊帕治疗，剂量为100 mg/每日（第2阶段）。在每个阶段结束后，受试者接受稳定同位素代谢研究，以确定VLDL-TG以及血浆apoC-II、apoC-III和apoE的分解代谢率（FCR）和生成率（PR）。在他汀类药物治疗的基础上，阿那曲泊帕由于VLDL-TG的FCR增加（29%；P = 0.002）而使VLDL-TG池减少。尽管在阿那曲泊帕单药治疗后VLDL-TG的FCR增加（41%；P = 0.11），但由于VLDL-TG的PR增加（39%；P = 0.014），VLDL-TG池未发生变化。阿那曲泊帕治疗后，apoC-II、apoC-III和apoE的池大小增加；然而，不同治疗组导致这些变化的机制有所不同。阿那曲泊帕通过增强VLDL的脂解潜力来增加VLDL-TG的FCR，从而在阿托伐他汀治疗的基础上降低VLDL-TG池。在接受阿那曲泊帕单药治疗的受试者中，由于VLDL-TG的PR随之增加，VLDL-TG池没有变化。
