Fibrates suppress bile acid synthesis via peroxisome proliferator-activated receptor-alpha-mediated downregulation of cholesterol 7 alpha-hydroxylase and sterol 27-hydroxylase expression
التفاصيل البيبلوغرافية
العنوان:
Fibrates suppress bile acid synthesis via peroxisome proliferator-activated receptor-alpha-mediated downregulation of cholesterol 7 alpha-hydroxylase and sterol 27-hydroxylase expression
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 alpha agonist Wy14,643 decreased bile acid synthesis in cultured rat hepatocytes and suppressed cholesterol 7 alpha -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 alpha -hydroxylase enzyme activity and mRNA. The functional involvement of PPARa in the suppression of both enzymes was proven with the use of PPAR alpha -null mice. In wild-type mice, ciprofibrate reduced cholesterol 7 alpha -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 alpha -null mice. A decreased bile acid production by PPAR alpha -mediated downregulation of cholesterol 7a-hydroxylase and sterol 27-hydroxylase may contribute to the increased risk of gallstone formation after fibrate treatment.
