Forkhead Box A3 and Bile Acid Metabolism

项目概要 项目摘要：胆汁酸 (BA) 由胆固醇合成。 BA 合成受到严格控制 预防疾病的发生，如胆汁淤积、胆结石、吸收不良、高胆固醇血症等。 BA 对于营养吸收很重要，并且还可以作为内分泌激素来调节代谢 体内平衡。 BAs 可以激活法尼醇 X 受体 (FXR) 和 TGR5，预防非酒精性脂肪肝 （NAFLD）、糖尿病和肥胖。 NAFLD 是全球最常见的慢性肝病之一， 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 代谢中的作用尚不清楚。同时使用功能获得和功能丧失 方法，我们表明 FOXA3 受 FXR 调节，可能调节 BA 代谢和代谢 体内平衡。在本项目中，我们计划研究肝脏FOXA3在BA反馈调节中的作用 代谢以及 BA 信号在 FOXA3 调节的代谢稳态中的作用。我们将使用一些 转基因小鼠以及功能获得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.