Submitted on September 17, 2007
Revised on February 12, 2008
Accepted on February 12, 2008
Liver receptor homolog 1 transcriptionally regulates human bile salt export pump expression
Xiulong Song, Rajani Kaimal, Bingfang Yan, and Ruitang Deng
Biomedical and Pharmaceutical Sciences, University of Rhode Island, Kingston, RI 02881
Corresponding Author: DengR{at}mail.uri.edu
Metabolic conversion of cholesterol into bile acids in liver is initiated by the rate-limiting cholesterol 7alpha-hydroxylase (CYP7A1) whereas bile salt export pump (BSEP) is responsible for canalicular secretion of bile acids. Liver receptor homolog 1 (LRH-1) is a key transcriptional factor required for the hepatic expression of CYP7A1. We hypothesized that LRH-1 was also involved in transcriptional regulation of BSEP. In support of our hypothesis, we found that overexpression of LRH-1 induced whereas knockdown of LRH-1 decreased BSEP expression. Consistent with its role in transcriptional regulation, LRH-1 dose-dependently transactivated BSEP promoter. In addition, such transactivation by LRH-1 was required for maximal induction of BSEP expression through the bile acid/farnesoid x receptor (FXR) activation pathway. Bioinformatic and mutational analysis led to identification of a functional LRH-1 responsive element (LRHRE) in the BSEP promoter. Specific binding of LRH-1 to the LRHRE and recruitment of LRH-1 to the BSEP promoter were demonstrated by EMSA and ChIP assays, respectively. In conclusion, LRH-1 transcriptionally activated BSEP promoter and functioned as a modulator in bile acid/FXR-mediated BSEP regulation. The results suggest that LRH-1 play a supporting role to FXR in maintaining hepatic bile acid levels by coordinately regulating CYP7A1 and BSEP for bile acid synthesis and elimination, respectively.
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