Nuclear receptor regulation of bile acid metabolism

 描述(申请人提供)：胆汁淤积，胆汁酸滞留在肝脏，是肝移植的主要原因。过量的胆汁酸具有细胞毒性，因此受到核受体法尼醇X受体(FXR)和小杂二聚体伙伴(SHP)的严格调控。胆汁酸是在肝脏中合成的，并分泌到肠道中以消化膳食脂肪。本研究旨在利用小鼠遗传模型，确定FXR和SHP在控制肝脏和肠道胆汁酸水平中的协同作用。该项目的成功完成将导致在上述组织中鉴定FXR和SHP驱动的转录基因网络。这些试验结果将使我们能够进行详细的分析，并提供对胆汁淤积基础的机械性见解。

 DESCRIPTION (provided by applicant): Cholestasis, retention of bile acids in the liver, is a leading cause for liver transplantation. Excess amounts of bile acids are cytotoxic and are therefore tightly regulated by nuclear receptors Farnesoid X Receptor (FXR) and Small Heterodimer Partner (SHP). Bile acids are synthesized in the liver and secreted into the intestine for digesting dietary fat. This proposal aims to determine coordinate role of FXR and SHP in controlling bile acid levels in liver and in intestine using genetic mouse models. Successful completion of this project would result in identification of FXR and SHP driven transcriptional gene networks in these above-mentioned tissues. These pilot results will enable us to perform detailed analysis and provide mechanistic insights into the underpinnings of cholestasis.