Mechanistic insights into isoform-dependent and species-specific regulation of bile salt export pump by farnesoid X receptor

• DOI: 10.1194/jlr.m038323
• Publication Date: 2013-09-04T04:47:06Z
• Authors: Xiulong Song; Yuan Chen; Leila Valanejad; Rajani Kaimal; Bingfang Yan; Matthew Stoner; Ruitang Deng
• Keywords: Farnesoid X receptor

Expression of bile salt export pump (BSEP) is regulated by the acid/farnesoid X receptor (FXR) signaling pathway. Two FXR isoforms, FXRα1 and FXRα2, are predominantly expressed in human liver. We previously showed that BSEP was isoform-dependently diminished with altered expression FXRα2 patients hepatocellular carcinoma. In this study, we demonstrate regulate through two distinct responsive elements (FXRE): IR1a IR1b. As predominant regulator, potently transactivated IR1a, while weakly a newly identified Relative affected vitro vivo. Electrophoretic mobility shift chromatin immunoprecipitation assays confirmed binding recruitment to IR1b IR1a. Sequence analysis concluded completely conserved among species, whereas exhibited apparent differences across species. variations were responsible for observed species difference transactivation FXRα2. conclusion, regulates an isoform-dependent species-specific manner FXREs, alteration relative isoform may be potential mechanism precisely response various physiological pathological conditions.