The peroxisome proliferator-activated receptor α (PPARα) regulates bile acid biosynthesis

Fibrates are a group of hypolipidemic agents that efficiently lower serum triglyceride levels by affecting the expression of many genes involved in lipid metabolism. These effects are exerted via the peroxisome proliferator-activated receptor alpha (PPAR alpha). In addition, fibrates also lower serum cholesterol levels, suggesting a possible link between the PPAR alpha and cholesterol metabolism. Bile acid formation represents an important pathway for elimination of cholesterol, and the sterol 12 alpha-hydroxylase is a branch-point enzyme in the bile acid biosynthetic pathway, which determines the ratio of cholic acid to chenodeoxycholic acid. Treatment of mice for 1 week with the peroxisome proliferator WY-14,643 or fasting for 24 h both induced the sterol 12 alpha-hydroxylase mRNA in liver. Using the PPAR alpha knockout mouse model, we show that the induction by both treatments was dependent on the PPAR alpha. A reporter plasmid containing a putative peroxisome proliferator-response element (PPRE) identified in the rat sterol 12 alpha-hydroxylase promoter region was activated by treatment with WY-14,643 in HepG2 cells, being dependent on co-transfection with a PPAR alpha expression plasmid, The rat 12 alpha-hydroxylase PPRE bound in vitro translated PPAR alpha and retinoid X receptor alpha, albeit weakly, in electrophoretic mobility shift assay, Treatment of wild-type mice with WY-14,643 for 1 week resulted in an increased relative amount of cholic acid, an effect that was abolished in the PPAR alpha null mice, verifying the functionality of the PPRE in vivo.