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标题：Peroxisome proliferator-activated receptor α (PPARα) and agonist inhibit cholesterol 7α-hydroxylase gene (CYP7A1) transcription
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作者：Maria Marrapodi ; John Y. L. Chiang
期刊名称：JLR Papers In Press
印刷版ISSN：0022-2275
电子版ISSN：1539-7262
出版年度：2000
卷号：41
期号：4
页码：514-520
语种：English
出版社：American Society for Biochemistry and Molecular Biology
摘要：Fibrates are widely used hypolipidemic drugs that regulate the expression of many genes involved in lipid metabolism by activating the peroxisome proliferator-activated receptor α (PPARα). The objective of this study was to investigate the mechanism of action of peroxisome proliferators and PPARα on the transcription of cholesterol 7α-hydroxylase, the rate-limiting enzyme in the conversion of cholesterol to bile acids in the liver. When cotransfected with the expression vectors for PPARα and RXRα, Wy14,643 reduced human and rat cholesterol 7α-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 PPARα/RXRα heterodimer to the DR1 sequence. PPARα and Wy14,643 did not affect HNF-4 binding to the DR1. However, Wy14,643 and PPARα/RXRα significantly reduced HNF-4 expression in HepG2 cells. These results suggest that PPARα and agonist repress cholesterol 7α-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 proliferator-activated receptor α (PPARα) and agonist inhibit cholesterol 7α-hydroxylase gene ( CYP7A1 ) transcription. J. Lipid Res. 2000. 41: 514–520.
关键词：bile acid synthesis ; gallstones ; peroxisome proliferators ; hypolipidemic drugs ; cytochrome P450 ; HNF-4