The hypolipidemic agent guggulsterone regulates the expression of human bile salt export pump: dominance of transactivation over farsenoid X receptor-mediated antagonism
Language: 
English
Short Title: 
The hypolipidemic agent guggulsterone regulates the expression of human bile salt export pump
Abstract: 

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.

Author(s): 
Deng, Ruitang
Yang, Dongfang
Radke, Amy
Yang, Jian
Yan, Bingfang
Item Type: 
Journal Article
Publication Title: 
The Journal of Pharmacology and Experimental Therapeutics
Journal Abbreviation: 
J. Pharmacol. Exp. Ther.
Publication Date: 
Mar 2007
Publication Year: 
2007
Pages: 
1153-1162
Volume: 
320
Issue: 
3
ISSN: 
0022-3565
DOI: 
10.1124/jpet.106.113837
Library Catalog: 
NCBI Published Medical (?)
Extra: 
PMID: 17135343 PMCID: PMC4114705

Turabian/Chicago Citation

Ruitang Deng, Dongfang Yang, Amy Radke, Jian Yang and Bingfang Yan. Mar 2007. "The hypolipidemic agent guggulsterone regulates the expression of human bile salt export pump: dominance of transactivation over farsenoid X receptor-mediated antagonism." The Journal of Pharmacology and Experimental Therapeutics 320: 3: 1153-1162. 10.1124/jpet.106.113837.

Wikipedia Citation

<ref> {{Cite journal | doi = 10.1124/jpet.106.113837 | issn = 0022-3565 | volume = 320 | pages = 1153-1162 | last = Deng | first = Ruitang | coauthors = Yang, Dongfang, Radke, Amy, Yang, Jian, Yan, Bingfang | title = The hypolipidemic agent guggulsterone regulates the expression of human bile salt export pump: dominance of transactivation over farsenoid X receptor-mediated antagonism | journal = The Journal of Pharmacology and Experimental Therapeutics | date = Mar 2007 | pmid = | pmc = }} </ref>