title: Anacetrapib promotes reverse cholesterol transport and bulk cholesterol excretion in Syrian golden hamsters.
abstract: Cholesteryl ester transfer protein (CETP) transfers cholesteryl ester (CE) and triglyceride between HDL and apoB-containing lipoproteins. Anacetrapib (ANA), a reversible inhibitor of CETP, raises HDL cholesterol (HDL-C) and lowers LDL cholesterol in dyslipidemic patients; however, the effects of ANA on cholesterol/lipoprotein metabolism in a dyslipidemic hamster model have not been demonstrated. To test whether ANA (60 mg/kg/day, 2 weeks) promoted reverse cholesterol transport (RCT), ³H-cholesterol-loaded macrophages were injected and (3)H-tracer levels were measured in HDL, liver, and feces. Compared to controls, ANA inhibited CETP (94%) and increased HDL-C (47%). ³H-tracer in HDL increased by 69% in hamsters treated with ANA, suggesting increased cholesterol efflux from macrophages to HDL. ³H-tracer in fecal cholesterol and bile acids increased by 90% and 57%, respectively, indicating increased macrophage-to-feces RCT. Mass spectrometry analysis of HDL from ANA-treated hamsters revealed an increase in free unlabeled cholesterol and CE. Furthermore, bulk cholesterol and cholic acid were increased in feces from ANA-treated hamsters. Using two independent approaches to assess cholesterol metabolism, the current study demonstrates that CETP inhibition with ANA promotes macrophage-to-feces RCT and results in increased fecal cholesterol/bile acid excretion, further supporting its development as a novel lipid therapy for the treatment of dyslipidemia and atherosclerotic vascular disease.
authors.affiliation: Department of Cardiovascular Diseases, Atherosclerosis, Merck Research Laboratories, Rahway, NJ, USA.
authors.forename: Jose
authors.initials: J
authors.lastname: Castro-Perez
authors.forename: François
authors.initials: F
authors.lastname: Briand
authors.forename: Karen
authors.initials: K
authors.lastname: Gagen
authors.forename: Sheng-Ping
authors.initials: SP
authors.lastname: Wang
authors.forename: Ying
authors.initials: Y
authors.lastname: Chen
authors.forename: David G
authors.initials: DG
authors.lastname: McLaren
authors.forename: Vinit
authors.initials: V
authors.lastname: Shah
authors.forename: Rob J
authors.initials: RJ
authors.lastname: Vreeken
authors.forename: Thomas
authors.initials: T
authors.lastname: Hankemeier
authors.forename: Thierry
authors.initials: T
authors.lastname: Sulpice
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Roddy
authors.forename: Brian K
authors.initials: BK
authors.lastname: Hubbard
authors.forename: Douglas G
authors.initials: DG
authors.lastname: Johns
mesh_terms: D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D002460:Cell Line; D002784:Cholesterol / Q000737:chemistry / Q000378:metabolism*; D053480:Cholesterol Ester Transfer Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D006224:Cricetinae; D050171:Dyslipidemias / Q000378:metabolism; D005243:Feces; D008075:Lipoproteins, HDL / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D023303:Oxazolidinones / Q000494:pharmacology*
chemical_list: D053480:Cholesterol Ester Transfer Proteins; D008075:Lipoproteins, HDL; D023303:Oxazolidinones; D002784:Cholesterol; C530884:anacetrapib