J. Lipid Res. Acyl Labeled PIP's available August 1, 2008
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Originally published In Press as doi:10.1194/jlr.M700417-JLR200 on February 12, 2008

This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
M700417-JLR200v1
49/5/973    most recent
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Google Scholar
Right arrow Articles by Song, X.
Right arrow Articles by Deng, R.
PubMed
Right arrow PubMed Citation
Right arrow Articles by Song, X.
Right arrow Articles by Deng, R.
Social Bookmarking
Add to CiteULike   Add to Complore   Add to Connotea   Add to Del.icio.us   Add to Digg   Add to Reddit   Add to Technorati  
What's this?
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

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{alpha}-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{alpha}-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{alpha} and Ostβ, organic solute transporters {alpha} and β; SHP, small heterodimer partner; siRNA, small interfering RNA


Add to CiteULike CiteULike   Add to Complore Complore   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us   Add to Digg Digg   Add to Reddit Reddit   Add to Technorati Technorati    What's this?




HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
 All ASBMB Journals   Journal of Biological Chemistry 
 Molecular and Cellular Proteomics   ASBMB Today 
Copyright © 2008 by the American Society for Biochemistry and Molecular Biology.