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40
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Text
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Pages
514–520
Issue
4
Volume
41
Dublin Core
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Title
A name given to the resource
Peroxisome proliferator-activated receptor alpha (PPARalpha) and agonist inhibit cholesterol 7alpha-hydroxylase gene (CYP7A1) transcription.
Publisher
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Journal of lipid research
Date
A point or period of time associated with an event in the lifecycle of the resource
2000
2000-04
Subject
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Humans; Animals; Binding Sites; Protein Binding; Rats; Gene Expression Regulation; Species Specificity; Liver/metabolism; Transcriptional Activation; Hepatocyte Nuclear Factor 4; Response Elements; *DNA-Binding Proteins; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; Retinoid X Receptors; Anticholesteremic Agents/pharmacology; Cholesterol 7-alpha-Hydroxylase/biosynthesis/*genetics; Clofibric Acid/pharmacology; Peroxisome Proliferators/pharmacology; Phosphoproteins/metabolism; Pyrimidines/pharmacology; Transcription Factors/*agonists/metabolism; Genes; Receptors; Models; Transcription; Genetic; Enzymologic; Reporter; Retinoic Acid/metabolism; Promoter Regions; Nucleic Acid; Cytoplasmic and Nuclear/*agonists; *Regulatory Sequences
Creator
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Marrapodi M; Chiang J Y
Description
An account of the resource
Fibrates are widely used hypolipidemic drugs that regulate the expression of many genes involved in lipid metabolism by activating the peroxisome proliferator-activated receptor alpha (PPARalpha). The objective of this study was to investigate the mechanism of action of peroxisome proliferators and PPARalpha on the transcription of cholesterol 7alpha-hydroxylase, the rate-limiting enzyme in the conversion of cholesterol to bile acids in the liver. When cotransfected with the expression vectors for PPARalpha and RXRalpha, Wy14,643 reduced human and rat cholesterol 7alpha-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 PPARalpha/RXRalpha heterodimer to the DR1 sequence. PPARalpha and Wy14,643 did not affect HNF-4 binding to the DR1. However, Wy14,643 and PPARalpha/RXRalpha significantly reduced HNF-4 expression in HepG2 cells. These results suggest that PPARalpha and agonist repress cholesterol 7alpha-hydroxylase activity by reducing the availability of
Rights
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Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
*DNA-Binding Proteins
*Regulatory Sequences
2000
Animals
Anticholesteremic Agents/pharmacology
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
Binding Sites
Chiang J Y
Cholesterol 7-alpha-Hydroxylase/biosynthesis/*genetics
Clofibric Acid/pharmacology
Cytoplasmic and Nuclear/*agonists
Department of Integrative Medical Sciences
Enzymologic
Gene Expression Regulation
Genes
Genetic
Hepatocyte Nuclear Factor 4
Humans
Journal of lipid research
Liver/metabolism
Marrapodi M
Models
NEOMED College of Medicine
Nucleic Acid
Peroxisome Proliferators/pharmacology
Phosphoproteins/metabolism
Promoter Regions
Protein Binding
Pyrimidines/pharmacology
Rats
Receptors
Reporter
Response Elements
Retinoic Acid/metabolism
Retinoid X Receptors
Species Specificity
Transcription
Transcription Factors/*agonists/metabolism
Transcriptional Activation