Regulation of Bile Acid Synthesis by Nuclear Receptors

2型糖尿病和肥胖与血脂异常、高血糖和胰岛素抵抗有关。肝脏 脂肪变性会导致胰岛素抵抗和非酒精性脂肪肝。胆汁酸在 通过激活核激素受体FXR和G来调节脂肪、葡萄糖和能量代谢 蛋白偶联受体TGR5。我们的中心假设是营养素、生长激素、昼夜节律 肠道微生物区系调节胆汁酸的合成以维持代谢动态平衡，并对此造成损害 调节反应导致血脂异常、糖耐量异常、胰岛素抵抗、脂肪肝 还有肥胖症。具体目标1将研究胆汁酸受体信号在肝脏调节中的作用 新陈代谢。生长激素-STAT5调节胆汁酸合成的机制及一例男性 将使用报告试验和染色质免疫沉淀试验对主要的CYP7B1进行研究 鉴定STAT5结合部位及STAT5对CYP7B1启动子的表观遗传调控。TGR5-/-、Cyp7a1-/- 腺病毒Cyp8b1高表达不同胆汁酸组成的小鼠及Cyp7a1、Cyp8b1和Cyp8b1 CYP7B1的表达将被用来研究生长激素的调节。特定目标2将研究胆汁的作用 脂肪肝、胰岛素抵抗和糖尿病中的酸受体信号。FXR和TGR5在体内的作用机制 将研究GLP-1的分泌和葡萄糖代谢。TGR5-/-小鼠将被用来研究垂直 袖状胃切除术对改善胰岛素抵抗、血脂异常及术后微生物群的影响。 具体目标3将研究代谢动态平衡中胆汁酸合成的昼夜节律。肝肠 微生物区系轴在胆汁酸代谢中起关键作用，昼夜节律紊乱与 代谢性疾病。生物失调与肥胖和炎症性肠道疾病有关。TGR5-/-、FXR-/- 和具有不同胆酸池大小和/或组成的Cyp7a1-/-将用于限时喂养 西方高脂/高胆固醇饮食中胆汁酸代谢和肠道微生物群的RNA研究 测序。Cyp7a1-/-、FXR-/-和TGR5-/-将用于确定白天的限时喂养 或夜间影响肝脏基因节律和总体胆汁酸动态平衡。

Type 2 diabetes and obesity is associated with dyslipidemia, hyperglycemia and insulin resistance. Hepatic steatosis contributes to insulin resistance and non-alcoholic fatty liver disease. Bile acids play a key role in regulation of lipid, glucose and energy metabolism by activating a nuclear hormone receptor FXR, and G protein-coupled receptor TGR5. Our central hypothesis is that nutrients, growth hormone, circadian rhythm and gut microbiota regulate bile acid synthesis to maintain metabolic homeostasis, and impairment of this regulatory response contributes to dyslipidemia, glucose intolerance, insulin resistance, fatty liver disease and obesity. Specific aim 1 will study the role of bile acid receptor signaling in regulation of hepatic metabolism. The mechanism of growth hormone-STAT5 regulation of bile acid synthesis and a male predominant Cyp7b1 will be studied using reporter assay and chromatin immuno- precipitation assay to identify STAT5 binding sites and epigenetic regulation of Cyp7b1 promoter by STAT5. Tgr5-/-, Cyp7a1-/- and adenovirus-Cyp8b1 over-expressed mice with different bile acid composition and Cyp7a1, Cyp8b1 and cyp7b1 expression will be used to study growth hormone regulation. Specific aim 2 will study the role of bile acid receptor signaling in fatty liver, insulin resistance and diabetes. The mechanism of FXR and TGR5 in GLP-1 secretion and glucose metabolism will be studied. Tgr5-/- mice will be used to study effect of vertical sleeve gastrectomy on improving insulin resistance, dyslipidemia and microbiome before and after surgery. Specific aim 3 will study circadian rhythm of bile acid synthesis in metabolic homeostasis. The liver-gut microbiota axis plays a critical role in bile acid metabolism and disturbance of circadian rhythm is linked to metabolic diseases. Dysbiosis is associated with obesity, and inflammatory bowel diseases. Tgr5-/-, FXR-/- and Cyp7a1-/- with different bile acid pool size and/or composition will be used for time-restricted feeding of Western high fat/high cholesterol diet to study bile acid metabolism and gut microbiome by RNA sequencing. Cyp7a1-/-, Fxr-/-, and Tgr5-/- will be used to determine how time-restricted feeding in day time or night time affect affect hepatic gene rhythms and overall bile acid homeostasis.