Dalcetrapib and anacetrapib differently impact HDL structure and function in rabbits and monkeys

作者：Brodeur Mathieu R; Rhainds David; Charpentier Daniel; Mihalache Avram Teodora; Mecteau Melanie; Brand Genevieve; Chaput Evelyne; Perez Anne; Niesor Eric J; Rheaume Eric; Maugeais Cyrille; Tardif Jean Claude^*

来源：The Journal of Lipid Research, 2017, 58(7): 1282-1291.

DOI：10.1194/jlr.M068940

• cholesteryl ester transfer protein
• high density lipoprotein
• efflux

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. alpha-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% (P < 0.01). The levels of. alpha- and pre beta-HDL were reduced by 16% (P < 0.001) and 69% (P < 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.

• 出版日期2017-7