Received for publication September 12, 2006.
Revised November 22, 2006.
Accepted for publication November 27, 2006.

Hypolipidemic Agent Guggulsterone Regulates the Expression of Human Bile Salt Export Pump: Dominance of Transactivation over FXR-Mediated antagonism

Abstract

Conversion of cholesterol to bile acids in the liver is initiated by the rate-limiting enzyme cholesterol 7-hydroxylase (CYP7A1) and excretion of bile acids from the liver is mediated by 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 acids-mediated activation of farsenoid X receptor (FXR). It is well established that hypolipidemic agent guggulsterone is an FXR antagonist and downregulates FXR target genes. In this study, however, we have demonstrated that guggulsterone synergistically induced the expression of BSEP in cells treated with FXR agonists bile acids. Dissection study located in the BSEP promoter an AP-1 site (activating protein-1) supporting the action of guggulsterone. Deletion or mutation of the AP-1 element 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 (JNK) and extracellular signal-regulated kinase (ERK) inhibitors markedly decreased the transactivation, suggesting an involvement of AP-1 activation pathway in the upregulation of BSEP by guggulsterone. Consistent with its FXR antagonism, guggulsterone antagonized bile acids-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 upregulation of BSEP expression by guggulsterone without activating FXR pathway as an FXR agonist does to suppress CYP7A1 expression represents a possible mechanism for guggulsterone-mediated hypolipidemic effect.

Key words: BSEP, Bile acids, FXR, Guggulsterone, Transcription, gene regulation

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