| Anacetrapib promotes reverse cholesterol transport and bulk cholesterol excretion in Syrian golden hamsters. | |
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MedLine Citation:
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PMID: 21841206 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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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-c and lowers LDL-c 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 (60mg/kg/day, 2 weeks) promoted reverse cholesterol transport (RCT), 3H-cholesterol-loaded macrophages were injected and 3H-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 cholesteryl ester. 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. |
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Authors:
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Jose Castro-Perez; Francois Briand; Karen Gagen; Sheng-Ping Wang; Ying Chen; David G McLaren; Vinit Shah; Rob J Vreeken; Thomas Hankemeier; Thierry Sulpice; Thomas P Roddy; Brian K Hubbard; Douglas G Johns |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2011-8-14 |
Journal Detail:
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Title: Journal of lipid research Volume: - ISSN: 0022-2275 ISO Abbreviation: - Publication Date: 2011 Aug |
Date Detail:
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Created Date: 2011-8-15 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 0376606 Medline TA: J Lipid Res Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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Merck Sharp & Dohme Corp.; |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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