MECHANISMS FOR ESTROGEN-MEDIATED TRANSREPRESSION OF HUMAN BILE SALT EXPORT PUMP

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. As a rate-limiting canalicular effluxer, the bile salt export pump (BSEP) controls both intrahepatic and biliary bile acid levels. Intrahepatic cholestasis of pregnancy (ICP) and gallstone disease are pathological conditions resulting from an imbalance of intrahepatic and biliary bile acids, respectively. ICP predominantly occurs during the third trimester of pregnancy, correlating with elevated estrogen levels. Gallstone disease exhibits clear gender preference, with women being 2-3 times more susceptible than men. Studies have demonstrated that estrogen plays a key role in the induction of the two diseases. In our preliminary studies, we found that estrogen transrepressed human BSEP via estrogen receptor-alpha (ERalpha), but the repression was not mediated through the classical estrogen responsive element (ERE)-dependent pathway. The objective of this proposal is to extend our preliminary findings and obtain additional evidence to support or refute our central hypothesis that down-regulation of BSEP expression by estrogen is a common risk factor for both ICP and gallstone disease and that such down-regulation is mediated through a novel nonclassical transrepression pathway. In this project, two specific aims will be pursued: Specific Aim 1 is to identify the cis-element in the BSEP promoter for estrogen to transrepress BSEP; and Specific Aim 2 is to determine the functional features of ERalpha required for estrogen to exert its repressive effect. Upon completion of the proposed study, we will have defined the novel cis-element in the BSEP promoter and functional features of ERalpha required for mediating estrogen's actions in ICP and gallstone disease.