|
Journal of Lipid Research, Vol. 41, 514-520, April 2000
Copyright © 2000 by Lipid Research, Inc.
Peroxisome proliferator-activated receptor (PPAR ) and agonist inhibit cholesterol 7 -hydroxylase gene (CYP7A1) transcription
Maria Marrapodia and
John Y. L. Chianga
a Department of Biochemistry and Molecular Pathology, Northeastern Ohio Universities College of Medicine, P.O. Box 95, Rootstown, OH 44272-0095
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]
|
 |
|
Copyright © 2000 by the American Society for Biochemistry and Molecular Biology.
|
Advertisement
Advertisement
|