Forkhead Box A3 and Bile Acid Metabolism

项目摘要 项目概述：胆汁酸(BAS)是由胆固醇合成的。BA的合成被严格控制在 预防胆汁淤积症、胆石症、吸收不良、高胆固醇血症等疾病的发生。 BA对营养吸收很重要，也是调节新陈代谢的内分泌激素 动态平衡。BAS可激活法尼醇X受体和TGR5预防非酒精性脂肪性肝病 (NAFLD)、糖尿病和肥胖症。非酒精性脂肪肝是全球最常见的慢性肝病之一， 通常与肥胖和糖尿病有关。叉头盒蛋白A3(FOXA3)是一种转录因子。到目前为止, 肝脏FOXA3在BA代谢中的作用完全未知。同时使用增益函数和损耗函数 我们发现FOXA3受FXR调控，可能调节BA的代谢和代谢 动态平衡。在本项目中，我们计划研究肝脏FOXA3在BA反馈调节中的作用 代谢及BA信号在FOXA3调节代谢动态平衡中的作用。我们将使用一些 转基因小鼠以及获得功能的方法来实现我们的目标。

Project Summary Project Summary: Bile acids (BAs) are synthesized from cholesterol. BA synthesis is tightly controlled to prevent incidence of diseases, such as cholestasis, gallstone disease, malabsorption, hypercholesterolemia, etc. BAs are important for nutrient absorption and also function as endocrine hormones to regulate metabolic homeostasis. BAs can activate farnesoid X receptor (FXR) and TGR5 to prevent non-alcoholic fatty liver disease (NAFLD), diabetes and obesity. NAFLD is one of the most common chronic liver diseases worldwide, and is often associated with obesity and diabetes. Forkhead box protein A3 (FOXA3) is a transcription factor. So far, the role of hepatic FOXA3 in BA metabolism is completely unknown. Using both gain- and loss-of-function approaches, we show that FOXA3 is regulated by FXR and may regulate BA metabolism and metabolic homeostasis. In this project, we plan to investigate the role of hepatic FOXA3 in feedback regulation of BA metabolism and the role of BA signaling in FOXA3-regulated metabolic homeostasis. We will use a number of genetically modified mice as well as gain-of-function approaches to accomplish our goals.