Fibrates are widely used hypolipidemic drugs that regulate the expression of many genes involved in lipid metabolism by activating the peroxisome proliferator-activated receptor ␣ (PPAR ␣ ). The objective of this study was to investigate the mechanism of action of peroxisome proliferators and PPAR ␣ on the transcription of cholesterol 7 ␣hydroxylase, the rate-limiting enzyme in the conversion of cholesterol to bile acids in the liver. When cotransfected with the expression vectors for PPAR ␣ and RXR ␣ , Wy14,643 reduced human and rat cholesterol 7 ␣ -hydroxylase gene ( CYP7A1 )/luciferase reporter activities by 88% and 43%, respectively, in HepG2 cells, but not in CV-1 or CHO cells. We have mapped the peroxisome proliferator response element (PPRE) to a conserved sequence containing the canonical AGGTCA direct repeats separated by one nucleotide (DR1). This DR1 sequence was mapped previously as a binding site for the hepatocyte nuclear factor 4 (HNF-4) which stimulates CYP7A1 transcription. Electrophoretic mobility shift assay (EMSA) showed no direct binding of in vitro synthesized PPAR ␣ /RXR ␣ heterodimer to the DR1 sequence. PPAR ␣ and Wy14,643 did not affect HNF-4 binding to the DR1. However, Wy14,643 and PPAR ␣ /RXR ␣ significantly reduced HNF-4 expression in HepG2 cells. These results suggest that PPAR ␣ and agonist repress cholesterol 7 ␣ -hydroxylase activity by reducing the availability of HNF-4 for binding to the DR-1 sequence and therefore attenuates the transactivation of CYP7A1 by HNF-4. -Marrapodi, M., and J. Y. L. Chiang. Peroxisome proliferatoractivated receptor ␣ (PPAR ␣ ) and agonist inhibit cholesterol 7 ␣ -hydroxylase gene ( CYP7A1 ) transcription.

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