| The hypolipidemic agent guggulsterone regulates the expression of human bile salt export pump: dominance of transactivation over farsenoid X receptor-mediated antagonism. | |
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MedLine Citation:
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PMID: 17135343 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Conversion of cholesterol to bile acids in the liver is initiated by the rate-limiting enzyme cholesterol 7alpha-hydroxylase (CYP7A1) and excretion of bile acids from the liver is mediated by the bile salt export pump (BSEP). The expression of CYP7A1 and BSEP is coordinately regulated by a negative feedback and positive feed-forward mechanism, respectively, through bile acid-mediated activation of farsenoid X receptor (FXR). It is well established that hypolipidemic agent guggulsterone is an FXR antagonist and down-regulates FXR target genes. In this study, however, we have demonstrated that guggulsterone synergistically induced the expression of BSEP in cells treated with FXR agonist bile acids. A dissection study located in the BSEP promoter an activating protein (AP)-1 site supporting the action of guggulsterone. Deletion or mutation of the AP-1 element was diminished, whereas insertion of the AP-1 element into a heterologous promoter enhanced activation of the promoter by guggulsterone. Selective c-Jun N-terminal kinase and extracellular signal-regulated kinase inhibitors markedly decreased the transactivation, suggesting an involvement of AP-1 activation pathway in the up-regulation of BSEP by guggulsterone. Consistent with its FXR antagonism, guggulsterone antagonized bile acid-mediated transactivation of BSEP promoter when the AP-1 element was disrupted. In conclusion, guggulsterone regulates BSEP expression through composite mechanisms, and the transactivation through the AP-1 element is dominant over the FXR-mediated antagonism. The up-regulation of BSEP expression by guggulsterone without activating FXR pathway as an FXR agonist to suppress CYP7A1 expression represents a possible mechanism for guggulsterone-mediated hypolipidemic effect. |
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Authors:
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Ruitang Deng; Dongfang Yang; Amy Radke; Jian Yang; Bingfang Yan |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2006-11-29 |
Journal Detail:
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Title: The Journal of pharmacology and experimental therapeutics Volume: 320 ISSN: 0022-3565 ISO Abbreviation: J. Pharmacol. Exp. Ther. Publication Date: 2007 Mar |
Date Detail:
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Created Date: 2007-02-16 Completed Date: 2007-04-09 Revised Date: 2012-05-28 |
Medline Journal Info:
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Nlm Unique ID: 0376362 Medline TA: J Pharmacol Exp Ther Country: United States |
Other Details:
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Languages: eng Pagination: 1153-62 Citation Subset: IM |
Affiliation:
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Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Fogarty Hall, 41 Lower College Road, Kingston, RI 02881, USA. DengR@mail.uri.edu |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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ATP-Binding Cassette Transporters
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biosynthesis*,
genetics Base Sequence Bile Acids and Salts / metabolism Cell Line, Tumor DNA-Binding Proteins / biosynthesis*, genetics Down-Regulation Hepatocytes / drug effects*, metabolism Humans Hypolipidemic Agents / pharmacology* Molecular Sequence Data Mutagenesis, Site-Directed NAD(P)H Dehydrogenase (Quinone) / genetics Pregnenediones / pharmacology* Promoter Regions, Genetic Receptors, Cytoplasmic and Nuclear / biosynthesis*, genetics Reverse Transcriptase Polymerase Chain Reaction Transcription Factor AP-1 / genetics Transcription Factors / biosynthesis*, genetics Transcriptional Activation* Transfection Up-Regulation |
| Grant Support | |
ID/Acronym/Agency:
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F05AT003019/AT/NCCAM NIH HHS; P20RR016457/RR/NCRR NIH HHS; R01ES07965/ES/NIEHS NIH HHS; R01GM61988/GM/NIGMS NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/ABCB11 protein, human; 0/ATP-Binding Cassette Transporters; 0/Bile Acids and Salts; 0/DNA-Binding Proteins; 0/Hypolipidemic Agents; 0/Pregnenediones; 0/Receptors, Cytoplasmic and Nuclear; 0/Transcription Factor AP-1; 0/Transcription Factors; 0/farnesoid X-activated receptor; 95975-55-6/pregna-4,17-diene-3,16-dione; EC 1.6.5.2/NAD(P)H Dehydrogenase (Quinone); EC 1.6.5.2/NQO1 protein, human |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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