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Biochemistry and molecular biology
Fibrates are a group of hypolipidemic agents which 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 (PPARa). In addition, fibrates also lower serum cholesterol levels, suggesting a possible link between the PPARa and cholesterol metabolism. Bile acid formation represents an important pathway for elimination of cholesterol, and the sterol 12a-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 one week with the peroxisome proliferator WY-14,643 or fasting for 24 hours both induced the sterol 12a- hydroxylase mRNA in liver. Using the PPARa knockout mouse model, we show that the induction by both treatments was dependent on the PPARa. A reporter plasmid containing a putative peroxisome proliferator-response element (PPRE) identified in the rat sterol 12a-hydroxylase promoter region was activated by treatment with WY-14,643 in HepG2 cells, being dependent on co-transfection with a PPARa expression plasmid. The rat 12a-hydroxylase PPRE bound in vitro translated PPARa and RXRa, albeit weakly, in electrophoretic mobility shift assay. Treatment of wild-type mice with WY-14,643 for one week resulted in an increased relative amount of cholic acid, an effect which was abolished in the PPARa null mice, verifying the functionality of the PPRE in vivo.