Fibrates suppress bile acid synthesis via peroxisome proliferator-activated receptor-alpha-mediated downregulation of cholesterol 7 alpha-hydroxylaseand sterol 27-hydroxylase expression

Fibrates are hypolipidemic drugs that affect the expression of genes involv ed in lipid metabolism by activating peroxisome proliferator-activated rece ptors (PPARs). Fibrate treatment causes adverse changes in biliary lipid co mposition and decreases bile acid excretion, leading to an increased incide nce of cholesterol gallstones. In this study, we investigated the effect of fibrates on bile acid synthesis. Ciprofibrate and the PPAR alpha agonist W y14,643 decreased bile acid synthesis in cultured rat hepatocytes and suppr essed cholesterol 7 alpha -hydroxylase and sterol 27-hydroxylase activities , paralleled by a similar reduction of the respective mRNAs. Treatment of r ats with 0.05% (wt/wt) ciprofibrate decreased cholesterol 7 alpha -hydroxyl ase enzyme activity and mRNA. The functional involvement of PPARa in the su ppression of both enzymes was proven with the use of PPAR alpha -null mice. In wild-type mice, ciprofibrate reduced cholesterol 7 alpha -hydroxylase a nd sterol 27-hydroxylase enzyme activities and mRNA. The decrease in mRNA o f both enzymes is regulated transcriptionally arid posttranscriptionally, r espectively, 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 alpha -null mice. A decreased bile acid produc tion by PPAR alpha -mediated downregulation of cholesterol 7a-hydroxylase a nd sterol 27-hydroxylase may contribute to the increased risk of gallstone formation after fibrate treatment.