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
Biology
Acetates
Animals
Anticholesteremic Agents
Bile Acids and Salts
Cells, Cultured
Cholesterol
Cholesterol 7-alpha-Hydroxylase
Cholesterol Esters
Enzyme Induction
Enzyme Inhibitors
Liver
Male
Rats
Rats, Wistar
RNA, Messenger
Sterol O-Acyltransferase
Sulfonic Acids
Triglycerides
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DOI
https://doi.org/10.1002/hep.510300230
TNO identifier
235121
ISSN
0270-9139
Source
Hepatology, 30 (2), 491-500
Document type
article