Print Email Facebook Twitter Acyl-coenzyme A:cholesterol acyltransferase inhibitor, avasimibe, stimulates bile acid synthesis and cholesterol 7α-hydroxylase in cultured rat hepatocytes and in vivo in the rat Title Acyl-coenzyme A:cholesterol acyltransferase inhibitor, avasimibe, stimulates bile acid synthesis and cholesterol 7α-hydroxylase in cultured rat hepatocytes and in vivo in the rat Author Post, S.M. Paul Zoeteweij, J. Bos, M.H.A. de Wit, E.C.M. Havinga, R. Kuipers, F. Princen, H.M.G. Gaubius instituut TNO Publication year 1999 Abstract Acyl-coenzyme A:cholesterol acyltransferase (ACAT) inhibitors are currently in clinical development as potential lipid-lowering and antiatherosclerotic agents. We investigated the effect of avasimibe (C1- 1011), a novel ACAT inhibitor, on bile acid synthesis and cholesterol 7α- hydroxylase in cultured rat hepatocytes and rats fed different diets. Avasimibe dose-dependently decreased ACAT activity in rat hepatocytes in the presence and absence of β-migrating very low-density lipoproteins (βVLDL) (by 93% and 75% at 10 μmol/L) and reduced intracellular storage of cholesteryl esters. Avasimibe (3 μmol/L) increased bile acid synthesis (2.9- fold) after preincubation with βVLDL and cholesterol 7α-hydroxylase activity (1.7-and 2.6-fold, with or without βVLDL), the latter paralleled by a similar induction of its messenger RNA (mRNA). Hepatocytes treated with avasimibe showed a shift from storage and secretion of cholesteryl esters to conversion of cholesterol into bile acids. In rats fed diets containing different amounts of cholesterol and cholate, avasimibe reduced plasma cholesterol (by 52% to 71%) and triglyceride levels (by 28% to 62%). Avasimibe did not further increase cholesterol 7α-hydroxylase activity and mRNA in cholesterol-fed rats, but prevented down-regulation by cholate. Avasimibe did not affect sterol 27-hydroxylase and oxysterol 7α-hydroxylase, 2 enzymes in the alternative pathway in bile acid synthesis. No increase in the ratio of biliary excreted cholesterol to bile acids was found, indicating that ACAT inhibition does not result in a more lithogenic bile. Avasimibe increases bile acid synthesis in cultured hepatocytes by enhancing the supply of free cholesterol both as substrate and inducer of cholesterol 7α- hydroxylase. These effects may partially explain the potent cholesterol- lowering effects of avasimibe in the rat. Subject BiologyAcetatesAnimalsAnticholesteremic AgentsBile Acids and SaltsCells, CulturedCholesterolCholesterol 7-alpha-HydroxylaseCholesterol EstersEnzyme InductionEnzyme InhibitorsLiverMaleRatsRats, WistarRNA, MessengerSterol O-AcyltransferaseSulfonic AcidsTriglycerides To reference this document use: http://resolver.tudelft.nl/uuid:0a19e4f1-bd75-414c-afd5-4997393d7e41 DOI https://doi.org/10.1002/hep.510300230 TNO identifier 235121 ISSN 0270-9139 Source Hepatology, 30 (2), 491-500 Document type article Files To receive the publication files, please send an e-mail request to TNO Library.