HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Marrapodi, M. Articles by Chiang, J. Y. L. Search for Related Content PubMed PubMed Citation Articles by Marrapodi, M. Articles by Chiang, J. Y. L. Social Bookmarking                      What's this?

Journal of Lipid Research, Vol. 41, 514-520, April 2000
Copyright © 2000 by Lipid Research, Inc.

Original Article

Peroxisome proliferator-activated receptor (PPAR) and agonist inhibit cholesterol 7-hydroxylase gene (CYP7A1) transcription

Correspondence to: John Y. L. Chiang

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 proliferator-activated receptor (PPAR) and agonist inhibit cholesterol 7-hydroxylase gene (CYP7A1) transcription. J. Lipid Res. 2000. 41: 514;–520.

Supplementary key words: bile acid synthesis, gallstones, peroxisome proliferators, hypolipidemic drugs, cytochrome P450, HNF-4

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				Y. Sun, L. Zhang, H. F. Gu, W. Han, M. Ren, F. Wang, B. Gong, L. Wang, H. Guo, W. Xin, et al. Peroxisome Proliferator-Activated Receptor-{alpha} Regulates the Expression of Pancreatic/Duodenal Homeobox-1 in Rat Insulinoma (INS-1) Cells and Ameliorates Glucose-Induced Insulin Secretion Impaired by Palmitate Endocrinology, February 1, 2008; 149(2): 662 - 671. [Abstract] [Full Text] [PDF]

				C. C. van der Hoogt, W. de Haan, M. Westerterp, M. Hoekstra, G. M. Dallinga-Thie, J. A. Romijn, H. M. G. Princen, J. W. Jukema, L. M. Havekes, and P. C. N. Rensen Fenofibrate increases HDL-cholesterol by reducing cholesteryl ester transfer protein expression J. Lipid Res., August 1, 2007; 48(8): 1763 - 1771. [Abstract] [Full Text] [PDF]

				Y. Li, O. Mezei, and N. F. Shay Human and Murine Hepatic Sterol-12-{alpha}-Hydroxylase and Other Xenobiotic Metabolism mRNA Are Upregulated by Soy Isoflavones J. Nutr., July 1, 2007; 137(7): 1705 - 1712. [Abstract] [Full Text] [PDF]

				S. Luci, B. Giemsa, H. Kluge, and K. Eder Clofibrate causes an upregulation of PPAR-{alpha} target genes but does not alter expression of SREBP target genes in liver and adipose tissue of pigs Am J Physiol Regulatory Integrative Comp Physiol, July 1, 2007; 293(1): R70 - R77. [Abstract] [Full Text] [PDF]

				C. G. Woods, J. P. Vanden Heuvel, and I. Rusyn Genomic Profiling in Nuclear Receptor-Mediated Toxicity Toxicol Pathol, June 1, 2007; 35(4): 474 - 494. [Abstract] [Full Text] [PDF]

				M. Shin, I. Kim, Y. Inoue, S. Kimura, and F. J. Gonzalez Regulation of Mouse Hepatic {alpha}-Amino-beta-Carboxymuconate-{epsilon}-Semialdehyde Decarboxylase, a Key Enzyme in the Tryptophan-Nicotinamide Adenine Dinucleotide Pathway, by Hepatocyte Nuclear Factor 4{alpha} and Peroxisome Proliferator-Activated Receptor {alpha} Mol. Pharmacol., October 1, 2006; 70(4): 1281 - 1290. [Abstract] [Full Text] [PDF]

				J. Xu, B. Christian, and D. B. Jump Regulation of Rat Hepatic L-Pyruvate Kinase Promoter Composition and Activity by Glucose, n-3 Polyunsaturated Fatty Acids, and Peroxisome Proliferator-activated Receptor-{alpha} Agonist J. Biol. Chem., July 7, 2006; 281(27): 18351 - 18362. [Abstract] [Full Text] [PDF]

				J. Miao, S. Fang, Y. Bae, and J. K. Kemper Functional Inhibitory Cross-talk between Constitutive Androstane Receptor and Hepatic Nuclear Factor-4 in Hepatic Lipid/Glucose Metabolism Is Mediated by Competition for Binding to the DR1 Motif and to the Common Coactivators, GRIP-1 and PGC-1{alpha} J. Biol. Chem., May 26, 2006; 281(21): 14537 - 14546. [Abstract] [Full Text] [PDF]

				J.-P. Pegorier, C. L. May, and J. Girard Control of Gene Expression by Fatty Acids J. Nutr., September 1, 2004; 134(9): 2444S - 2449S. [Abstract] [Full Text] [PDF]

				G. F. Gbaguidi and L. B. Agellon The inhibition of the human cholesterol 7{alpha}-hydroxylase gene (CYP7A1) promoter by fibrates in cultured cells is mediated via the liver x receptor {alpha} and peroxisome proliferator-activated receptor {alpha} heterodimer Nucleic Acids Res., February 11, 2004; 32(3): 1113 - 1121. [Abstract] [Full Text] [PDF]

				O. Barbier, D. Duran-Sandoval, I. Pineda-Torra, V. Kosykh, J.-C. Fruchart, and B. Staels Peroxisome Proliferator-activated Receptor {alpha} Induces Hepatic Expression of the Human Bile Acid Glucuronidating UDP-glucuronosyltransferase 2B4 Enzyme J. Biol. Chem., August 29, 2003; 278(35): 32852 - 32860. [Abstract] [Full Text] [PDF]

				S. L. Ripp, K. C. Falkner, M. L. Pendleton, V. Tamasi, and R. A. Prough Regulation of CYP2C11 by Dehydroepiandrosterone and Peroxisome Proliferators: Identification of the Negative Regulatory Region of the Gene Mol. Pharmacol., July 1, 2003; 64(1): 113 - 122. [Abstract] [Full Text] [PDF]

				D. Jung, M. Fried, and G. A. Kullak-Ublick Human Apical Sodium-dependent Bile Salt Transporter Gene (SLC10A2) Is Regulated by the Peroxisome Proliferator-activated Receptor alpha J. Biol. Chem., August 16, 2002; 277(34): 30559 - 30566. [Abstract] [Full Text] [PDF]

				S. M. Post, H. Duez, P. P. Gervois, B. Staels, F. Kuipers, and H. M.G. Princen Fibrates Suppress Bile Acid Synthesis via Peroxisome Proliferator-Activated Receptor-{alpha}-Mediated Downregulation of Cholesterol 7{alpha}-Hydroxylase and Sterol 27-Hydroxylase Expression Arterioscler. Thromb. Vasc. Biol., November 1, 2001; 21(11): 1840 - 1845. [Abstract] [Full Text] [PDF]

				R. A. Memon, A. H. Moser, J. K. Shigenaga, C. Grunfeld, and K. R. Feingold In Vivo and in Vitro Regulation of Sterol 27-Hydroxylase in the Liver during the Acute Phase Response. POTENTIAL ROLE OF HEPATOCYTE NUCLEAR FACTOR-1 J. Biol. Chem., August 3, 2001; 276(32): 30118 - 30126. [Abstract] [Full Text] [PDF]