文章基本信息

标题：Liver receptor homolog 1 transcriptionally regulates human bile salt export pump expression
本地全文：下载
作者：Xiulong Song ; Rajani Kaimal ; Bingfang Yan 等
期刊名称：JLR Papers In Press
印刷版ISSN：0022-2275
电子版ISSN：1539-7262
出版年度：2008
卷号：49
期号：5
页码：973-984
DOI：10.1194/jlr.M700417-JLR200
语种：English
出版社：American Society for Biochemistry and Molecular Biology
摘要：The metabolic conversion of cholesterol into bile acids in liver is initiated by the rate-limiting cholesterol 7α-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.