Forkhead Box A3 and Bile Acid Metabolism

叉头盒 A3 和胆汁酸代谢

• 批准号: 10083739
• 负责人: Yanqiao Zhang
• 金额: $ 53.56万
• 依托单位: NORTHEAST OHIO MEDICAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10083739
• 关键词: Agonist; Anabolism; Bile Acid Biosynthesis Pathway; Bile Acids; Blood Circulation; CYP7A1 gene; CYP8B1 gene; Cholestasis; Cholesterol; Cholesterol 7-alpha-Monooxygenase; Coupled; Data; Diabetes Mellitus; Diet; Dietary Fats; Disease; Endocrine; Energy Metabolism; Enzymes; FGF19 gene; Fat-Soluble Vitamin; Fatty Liver; Fatty acid glycerol esters; Feedback; Fibroblast Growth Factor; G-Protein-Coupled Receptors; GPBAR1 gene; GTP-Binding Proteins; Generations; Goals; Health; Hepatic; Hepatocyte; High Fat Diet; Homeostasis; Hormones; Human; Impairment; Incidence; Inflammation; Insulin Resistance; Intestines; Lead; Lipids; Liver; MAP Kinase Gene; MAPK8 gene; Malabsorption Syndromes; Mediating; Metabolic; Metabolic Diseases; Metabolic stress; Mitogen-Activated Protein Kinases; Mixed Function Oxygenases; Mus; Nuclear Hormone Receptors; Obese Mice; Obesity; Patients; Play; Production; Protein Hormone Receptor; Proteins; Receptor Activation; Regulation; Role; Signal Transduction; Sterols; Testing; Transgenic Organisms; Vitamin D3 Receptor; Work; absorption; base; bile acid metabolism; blood glucose regulation; chronic liver disease; diabetic; diet-induced obesity; gain of function; gallstone disease; glucose metabolism; hypercholesterolemia; improved; knock-down; lipid metabolism; liver metabolism; loss of function; member; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; novel; nutrient absorption; overexpression; pregnane X receptor; prevent; receptor; transcription factor; treatment strategy; uptake

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.

项目摘要 胆汁酸（Bile Acids，BAs）是由胆固醇合成的。BA合成受到严格控制， 预防胆汁淤积、胆结石、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，也作为内分泌激素调节代谢 体内平衡。BA可以激活法尼醇X受体（FXR）和TGR 5，以预防非酒精性脂肪肝疾病 （NAFLD）、糖尿病和肥胖。NAFLD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（FOXA 3）是一种转录因子。到目前为止， 肝FOXA 3在BA代谢中的作用完全未知。同时使用功能增益和功能损失 方法，我们表明FOXA 3受FXR调节，并可能调节BA代谢和代谢 体内平衡。在本项目中，我们计划研究肝脏FOXA 3在BA反馈调节中的作用， 代谢和BA信号转导在FOXA 3调节的代谢稳态中的作用。我们将使用一些 转基因小鼠以及获得功能的方法来实现我们的目标。