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 脂肪变性导致胰岛素抵抗和非酒精性脂肪肝病。胆汁酸在 通过激活核激素受体FXR和G调节脂质、葡萄糖和能量代谢 蛋白偶联受体TGR 5。我们的核心假设是营养素，生长激素，昼夜节律 和肠道微生物群调节胆汁酸合成以维持代谢稳态， 调节反应导致血脂异常、葡萄糖耐受不良、胰岛素抵抗、脂肪肝 和肥胖。具体目标1将研究胆汁酸受体信号转导在肝细胞凋亡调控中的作用。 新陈代谢.生长抑素-STAT 5调控胆汁酸合成的机制及雄性 主要Cyp 7 b1将使用报告分析和染色质免疫沉淀分析进行研究， 鉴定STAT 5结合位点和STAT 5对Cyp 7 b1启动子表观遗传调控。Tgr 5-/-，Cyp7a1-/- 和腺病毒-Cyp 8b 1过表达的小鼠具有不同的胆汁酸组成和Cyp 7a 1，Cyp 8b 1和 CYP 7 B1表达将用于研究生长激素调节。具体目标2将研究胆汁的作用 脂肪肝、胰岛素抵抗和糖尿病中的酸性受体信号传导。FXR和TGR 5在乳腺癌中的作用机制 将研究GLP-1分泌和葡萄糖代谢。Tgr 5-/-小鼠将用于研究垂直注射的效果。 袖状胃切除术改善胰岛素抵抗，血脂异常和手术前后的微生物组。 具体目标3将研究代谢稳态中胆汁酸合成的昼夜节律。肝肠 微生物群轴在胆汁酸代谢中起着关键作用，昼夜节律的紊乱与 代谢性疾病生态失调与肥胖和炎症性肠病有关。Tgr 5-/-、FXR-/- 和Cyp 7a 1-/-具有不同的胆汁酸池大小和/或组成将用于时间限制的喂养 西方高脂肪/高胆固醇饮食通过RNA研究胆汁酸代谢和肠道微生物组 测序Cyp 7a 1-/-、Fxr-/-和Tgr 5-/-将用于确定在白天时间限制喂养 或夜间影响肝脏基因节律和整体胆汁酸稳态。

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.