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Journal of Lipid Research, Vol. 49, 973-984, May 2008
Copyright © 2008 by American Society for Biochemistry and Molecular Biology

Liver receptor homolog 1 transcriptionally regulates human bile salt export pump expression^*

Xiulong Song, Rajani Kaimal, Bingfang Yan and Ruitang Deng¹

Department of Biomedical and Pharmaceutical Sciences, Center for Pharmacogenomics and Molecular Therapy, College of Pharmacy, University of Rhode Island, Kingston, RI

^* This work was partially supported by funding from the New Investigator Program for Pharmacy Faculty, American Association of Colleges of Pharmacy; by a Medical Research Grant from the Rhode Island Foundation; by Rhode Island-IDeA Network of Biomedical Research Excellence Grant P20 RR-016457 from the National Center for Research Resources/National Institutes of Health; and by a Faculty Research Development Grant, University of Rhode Island. B.Y. was supported by National Institutes of Health Grants R01 GM-61988 and R01 ES-07965.

Published, JLR Papers in Press, February 12, 2008.

¹ To whom correspondence should be addressed. e-mail: dengr{at}mail.uri.edu

The metabolic conversion of cholesterol into bile acids in liver is initiated by the rate-limiting cholesterol 7-hydroxylase (CYP7A1), whereas the bile salt export pump (BSEP) is responsible for the 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 the 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 the 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 the identification of a functional liver receptor homolog 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 electrophoretic mobility shift assay and chromatin immunoprecipitation assay, respectively. In conclusion, LRH-1 transcriptionally activated the BSEP promoter and functioned as a modulator in bile acid/FXR-mediated BSEP regulation. These results suggest that LRH-1 plays a supporting role to FXR in maintaining hepatic bile acid levels by coordinately regulating CYP7A1 and BSEP for bile acid synthesis and elimination, respectively.

Supplementary key words bile acids • bile acid synthesis and elimination • cholesterol • cholesterol metabolism • farnesoid X receptor • small heterodimer partner • nuclear receptors

Abbreviations: ASBT, apical sodium-dependent bile acid transporter; BSEP, bile salt export pump; CDCA, chenodeoxycholic acid; ChIP, chromatin immunoprecipitation; CYP7A1, cholesterol 7-hydroxylase; eGFP, enhanced green fluorescent protein; EMSA, electrophoretic mobility shift assay; FXR, farnesoid X receptor; LRH-1, liver receptor homolog 1; LRHRE, liver receptor homolog 1-responsive element; Ost and Ostβ, organic solute transporters and β; SHP, small heterodimer partner; siRNA, small interfering RNA

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