doi: 10.1161/hq1101.098228
© 2001 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Fibrates Suppress Bile Acid Synthesis via Peroxisome Proliferator–Activated Receptor-
–Mediated Downregulation of Cholesterol 7-Hydroxylase and Sterol 27-Hydroxylase Expression
From the Gaubius Laboratory (S.M.P., P.P.G., H.M.G.P.), TNO-PG, Leiden, the Netherlands; Départment d’Athérosclérose (H.D., B.S.), Institut Pasteur de Lille and Faculté de Pharmacie, Université de Lille II, Lille, France; and Groningen University Institute for Drug Exploration (F.K.), Center for Liver, Digestive and Metabolic Diseases, University of Groningen, Groningen, the Netherlands.
Correspondence to Dr Hans M.G. Princen, Gaubius Laboratory, TNO-PG, PO Box 2215, 2301 CE, Leiden, Netherlands. E-mail JMG.Princen{at}PG.TNO.NL
Abstract—— Fibrates are hypolipidemic drugs that affect the expression of genes involved in lipid metabolism by activating peroxisome proliferator–activated receptors (PPARs). Fibrate treatment causes adverse changes in biliary lipid composition and decreases bile acid excretion, leading to an increased incidence of cholesterol gallstones. In this study, we investigated the effect of fibrates on bile acid synthesis. Ciprofibrate and the PPAR
agonist Wy14,643 decreased bile acid synthesis in cultured rat hepatocytes and suppressed cholesterol 7-hydroxylase and sterol 27-hydroxylase activities, paralleled by a similar reduction of the respective mRNAs. Treatment of rats with 0.05% (wt/wt) ciprofibrate decreased cholesterol 7-hydroxylase enzyme activity and mRNA. The functional involvement of PPAR in the suppression of both enzymes was proven with the use of PPAR-null mice. In wild-type mice, ciprofibrate reduced cholesterol 7-hydroxylase and sterol 27-hydroxylase enzyme activities and mRNA. The decrease in mRNA of both enzymes is regulated transcriptionally and posttranscriptionally, respectively, resulting in a decline in the output of fecal bile acids (-45%) and a 3-fold increase in fecal cholesterol secretion. These effects were completely abolished in PPAR-null mice. A decreased bile acid production by PPAR-mediated downregulation of cholesterol 7-hydroxylase and sterol 27-hydroxylase may contribute to the increased risk of gallstone formation after fibrate treatment.
Key Words: PPAR-null mice • rats • hepatocytes • cholesterol excretion
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