Document Detail

The hypolipidemic agent guggulsterone regulates the expression of human bile salt export pump: dominance of transactivation over farsenoid X receptor-mediated antagonism.
MedLine Citation:
PMID:  17135343     Owner:  NLM     Status:  MEDLINE    
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.
Ruitang Deng; Dongfang Yang; Amy Radke; Jian Yang; Bingfang Yan
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2006-11-29
Journal Detail:
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:
Created Date:  2007-02-16     Completed Date:  2007-04-09     Revised Date:  2012-05-28    
Medline Journal Info:
Nlm Unique ID:  0376362     Medline TA:  J Pharmacol Exp Ther     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1153-62     Citation Subset:  IM    
Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Fogarty Hall, 41 Lower College Road, Kingston, RI 02881, USA.
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MeSH Terms
ATP-Binding Cassette Transporters / biosynthesis*,  genetics
Base Sequence
Bile Acids and Salts / metabolism
Cell Line, Tumor
DNA-Binding Proteins / biosynthesis*,  genetics
Hepatocytes / drug effects*,  metabolism
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*
Grant Support
Reg. No./Substance:
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 Dehydrogenase (Quinone); EC protein, human

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