Brodeur Mathieu R, Rhainds David, Charpentier Daniel, Mihalache-Avram Teodora, Mecteau Mélanie, Brand Geneviève, Chaput Evelyne, Perez Anne, Niesor Eric J, Rhéaume Eric, Maugeais Cyrille, Tardif Jean-Claude
Montreal Heart Institute, Montreal, Quebec, Canada.
F. Hoffmann-La Roche Ltd., Basel, Switzerland.
J Lipid Res. 2017 Jul;58(7):1282-1291. doi: 10.1194/jlr.M068940. Epub 2017 May 17.
Inhibition of cholesteryl ester transfer protein (CETP) increases HDL cholesterol (HDL-C) levels. However, the circulating CETP level varies and the impact of its inhibition in species with high CETP levels on HDL structure and function remains poorly characterized. This study investigated the effects of dalcetrapib and anacetrapib, the two CETP inhibitors (CETPis) currently being tested in large clinical outcome trials, on HDL particle subclass distribution and cholesterol efflux capacity of serum in rabbits and monkeys. New Zealand White rabbits and vervet monkeys received dalcetrapib and anacetrapib. In rabbits, CETPis increased HDL-C, raised small and large α-migrating HDL, and increased ABCA1-induced cholesterol efflux. In vervet monkeys, although anacetrapib produced similar results, dalcetrapib caused opposite effects because the LDL-C level was increased by 42% and HDL-C decreased by 48% ( < 0.01). The levels of α- and preβ-HDL were reduced by 16% ( < 0.001) and 69% ( < 0.01), resulting in a decrease of the serum cholesterol efflux capacity. CETPis modulate the plasma levels of mature and small HDL in vivo and consequently the cholesterol efflux capacity. The opposite effects of dalcetrapib in different species indicate that its impact on HDL metabolism could vary greatly according to the metabolic environment.
抑制胆固醇酯转运蛋白（CETP）可提高高密度脂蛋白胆固醇（HDL-C）水平。然而，循环中的CETP水平存在差异，在CETP水平较高的物种中抑制该蛋白对HDL结构和功能的影响仍未得到充分表征。本研究调查了目前正在大型临床结局试验中进行测试的两种CETP抑制剂（CETPis）——达塞曲匹和阿那曲匹，对兔和猴血清中HDL颗粒亚类分布及胆固醇流出能力的影响。新西兰白兔和黑长尾猴接受了达塞曲匹和阿那曲匹治疗。在兔中，CETPis提高了HDL-C水平，增加了小的和大的α迁移HDL，并增强了ABCA1诱导的胆固醇流出。在黑长尾猴中，尽管阿那曲匹产生了类似的结果，但达塞曲匹却产生了相反的效果，因为低密度脂蛋白胆固醇（LDL-C）水平升高了42%，而HDL-C水平降低了48%（<0.01）。α-HDL和前β-HDL水平分别降低了16%（<0.001）和69%（<0.01），导致血清胆固醇流出能力下降。CETPis在体内调节成熟HDL和小HDL的血浆水平，从而调节胆固醇流出能力。达塞曲匹在不同物种中产生的相反效果表明，其对HDL代谢的影响可能会因代谢环境的不同而有很大差异。
