1
40
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Text
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<a href="http://doi.org/10.1152/ajpgi.00258.2004" target="_blank" rel="noreferrer noopener">http://doi.org/10.1152/ajpgi.00258.2004</a>
Pages
G74–84
Issue
1
Volume
288
Dublin Core
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Title
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Mechanism of rifampicin and pregnane X receptor inhibition of human cholesterol 7 alpha-hydroxylase gene transcription.
Publisher
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American journal of physiology. Gastrointestinal and liver physiology
Date
A point or period of time associated with an event in the lifecycle of the resource
2005
2005-01
Subject
The topic of the resource
Bile Acids and Salts/pharmacology; Cholestasis/*physiopathology; Cholesterol 7-alpha-Hydroxylase/*biosynthesis/pharmacology; Cultured; Cytoplasmic and Nuclear/*physiology; DNA-Binding Proteins/pharmacology; Enzyme Inhibitors/*pharmacology; Genetic; Glucocorticoid; Hepatoblastoma/pathology; Hepatocyte Nuclear Factor 4; Humans; Liver Neoplasms/pathology; Messenger/analysis/biosynthesis; Phosphoproteins/pharmacology; Pregnane X Receptor; Receptors; Rifampin/*pharmacology; RNA; Steroid/*physiology; Transcription; Transcription Factors/pharmacology; Tumor Cells; Up-Regulation
Creator
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Li Tiangang; Chiang John Y L
Description
An account of the resource
Bile acids, steroids, and drugs activate steroid and xenobiotic receptor pregnane X receptor (PXR; NR1I2), which induces human cytochrome P4503A4 (CYP3A4) in drug metabolism and cholesterol 7 alpha-hydroxylase (CYP7A1) in bile acid synthesis in the liver. Rifampicin, a human PXR agonist, inhibits bile acid synthesis and has been used to treat cholestatic diseases. The objective of this study is to elucidate the mechanism by which PXR inhibits CYP7A1 gene transcription. The mRNA expression levels of CYP7A1 and several nuclear receptors known to regulate the CYP7A1 gene were assayed in human primary hepatocytes by quantitative real-time PCR (Q-PCR). Rifampicin reduced CYP7A1 and small heterodimer partner (SHP; NR02B) mRNA expression suggesting that SHP was not involved in PXR inhibition of CYP7A1. Rifampicin inhibited CYP7A1 reporter activity and a PXR binding site was localized to the bile acid response element-I. Mammalian two-hybrid assays revealed that PXR interacted with hepatic nuclear factor 4 alpha (HNF4 alpha, NR2A1) and rifampicin was required. Coimmunoprecipitation assay confirmed PXR interaction with HNF4 alpha. PXR also interacted with peroxisome proliferator-activated receptor gamma coactivator (PGC-1 alpha), which interacted with HNF4 alpha and induced CYP7A1 gene transcription. Rifampicin enhanced PXR interaction with HNF4 alpha and reduced PGC-1 alpha interaction with HNF4 alpha. Chromatin immunoprecipitation assay showed that PXR, HNF4 alpha, and PGC-1 alpha bound to CYP7A1 chromatin, and rifampicin dissociated PGC-1 alpha from chromatin. These results suggest that activation of PXR by rifampicin promotes PXR interaction with HNF4 alpha and blocks PGC-1 alpha activation with HNF4 alpha and results in inhibition of CYP7A1 gene transcription. Rifampicin inhibition of bile acid synthesis may be a protective mechanism against drug and bile acid-induced cholestasis.
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<a href="http://doi.org/10.1152/ajpgi.00258.2004" target="_blank" rel="noreferrer noopener">10.1152/ajpgi.00258.2004</a>
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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).
2005
American journal of physiology. Gastrointestinal and liver physiology
Bile Acids and Salts/pharmacology
Chiang John Y L
Cholestasis/*physiopathology
Cholesterol 7-alpha-Hydroxylase/*biosynthesis/pharmacology
Cultured
Cytoplasmic and Nuclear/*physiology
Department of Integrative Medical Sciences
DNA-Binding Proteins/pharmacology
Enzyme Inhibitors/*pharmacology
Genetic
Glucocorticoid
Hepatoblastoma/pathology
Hepatocyte Nuclear Factor 4
Humans
Li Tiangang
Liver Neoplasms/pathology
Messenger/analysis/biosynthesis
NEOMED College of Medicine
Phosphoproteins/pharmacology
Pregnane X Receptor
Receptors
Rifampin/*pharmacology
RNA
Steroid/*physiology
Transcription
Transcription Factors/pharmacology
Tumor Cells
Up-Regulation
-
Text
A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text.
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n/a
Rights
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
Pages
2483-2491
Issue
12
Volume
38
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Dublin Core
The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/.
Title
A name given to the resource
Hormonal regulation of cholesterol 7 alpha-hydroxylase specific activity, mRNA levels, and transcriptional activity in vivo in the rat
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
1997
1997-12
Subject
The topic of the resource
bile-acid biosynthesis; Biochemistry & Molecular Biology; cholesterol; cholesterol 7 alpha-hydroxylase; cultures; gene; gene cyp7; glucocorticoid; hepatic cholesterol; hepatocyte cultures; liver; messenger-rna levels; monolayer-cultures; primary; protein-kinase-c; regulation; sterol 27-hydroxylase; thyroid; thyroid-hormone
Creator
An entity primarily responsible for making the resource
Pandak W M; Heuman D M; Redford K; Stravitz R T; Chiang J Y L; Hylemon P B; Vlahcevic Z R
Description
An account of the resource
In primary cultures of rat hepatocytes, transcription of the cholesterol 7 alpha-hydroxylase gene is induced synergistically by glucocorticoid and thyroid hormones. The objective of the present study was to evaluate the role of glucocorticoid and thyroid hormones in the maintenance of cholesterol 7 alpha-hydroxylase gene expression in vivo. Male Sprague-Dawley rats underwent adrenalectomy (A), thyroidectomy (T), adrenalectomy + thyroidectomy (A + T), hypophysectomy (H), or sham surgery (paired controls). Ten days post surgery, livers were harvested and cholesterol 7 alpha-hydroxylase specific activity, steady-state mRNA levels, and transcriptional activity were determined. Serum corticosterone levels were <2% of paired controls in A, A + T and H rats. Free thyroxine index was <32% of paired controls in rats with T and H. When compared to sham-operated controls, A + T and H led to decreases in cholesterol 7 alpha-hydroxylase specific activities of 44 +/- 8% and 57 +/- 3%, respectively (P < 0.03 and < 0.05). Similar changes were observed in cholesterol 7 alpha-hyroxylase steady-state mRNA levels, which decreased by 43 +/- 10% (P < 0.001) and 56 +/- 19% (P < 0.05), respectively. Cholesterol 7 alpha-hydroxylase transcriptional activity in A + T and H rats decreased by 34 +/- 11% (P < 0.01) and 61 +/- 4% (P < 0.001), respectively. The observed decreases were greater after H than after A + T, suggesting the possibility that another pituitary hormone plays a role in regulation of cholesterol 7 alpha-hydroxylase. Thyroidectomy alone led to a decrease in cholesterol 7 alpha-hydroxylase specific activity of 37 +/- 7% (P < 0.05) and a trend toward decreased steady-state mRNA levels (21 +/- 12%; P = ns). Adrenalectomy did not significantly decrease cholesterol 7 alpha-hydroxylase specific activity or mRNA levels. Neither thyroidectomy nor adrenalectomy alone affected transcriptional activity. We conclude that under physiologic circumstances, full expression of the cholesterol 7 alpha-hydroxylase gene requires synergistic action of glucocorticoids and thyroid hormone.
Identifier
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n/a
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Journal Article
1997
bile-acid biosynthesis
Biochemistry & Molecular Biology
Chiang J Y L
Cholesterol
cholesterol 7 alpha-hydroxylase
cultures
gene
gene cyp7
Glucocorticoid
hepatic cholesterol
hepatocyte cultures
Heuman D M
Hylemon P B
Journal Article
Journal of lipid research
Liver
messenger-rna levels
monolayer-cultures
Pandak W M
primary
protein-kinase-c
Redford K
regulation
sterol 27-hydroxylase
Stravitz R T
thyroid
thyroid-hormone
Vlahcevic Z R