Regulation of Bile Acid Synthesis by Nuclear Receptors

核受体对胆汁酸合成的调节

• 批准号: 9923618
• 负责人: JOHN Y. L. CHIANG
• 金额: $ 36.27万
• 依托单位: NORTHEAST OHIO MEDICAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9923618
• 关键词: ARNTL gene; Acetylation; Adenoviruses; Affect; Agonist; Animal Experiments; Animals; Bariatrics; Bile Acid Biosynthesis Pathway; Bile Acids; Binding Sites; Biological Assay; Bypass; CYP8B1 gene; Carbohydrates; Cholesterol; Circadian Dysregulation; Circadian Rhythms; Collaborations; Colon; Data; Diabetes Mellitus; Diet; Disease remission; Dyslipidemias; Eating; Energy Metabolism; FGF21 gene; Fasting; Fatty Liver; Fatty acid glycerol esters; G-Protein-Coupled Receptors; GPBAR1 gene; Gastrectomy; Gastric Bypass; Gene Expression; Genes; Genetic; Gluconeogenesis; Glucose Intolerance; Growth; Hepatic; High Fat Diet; Homeostasis; Hydrophobicity; Hyperglycemia; IACUC; Impairment; Inflammatory Bowel Diseases; Insulin Resistance; Link; Lipids; Liver; Liver diseases; Malignant Neoplasms; Metabolic; Metabolic Diseases; Methylation; Michigan; Molecular; Mus; Non-Insulin-Dependent Diabetes Mellitus; Nuclear Hormone Receptors; Nuclear Receptors; Nutrient; Obesity; Operative Surgical Procedures; Pathway interactions; Patients; Pharmaceutical Preparations; Play; Predisposition; Protocols documentation; Receptor Signaling; Regulation; Reporter; Research Personnel; Role; Serum; Signal Transduction; Somatotropin; Stat5 protein; Testing; Therapeutic; Time; Time-restricted feeding; Universities; adenoviral-mediated; bariatric surgery; base; bile acid metabolism; chromatin immunoprecipitation; dysbiosis; epigenetic regulation; farnesoid X-activated receptor; feeding; feeding schedule; glucagon-like peptide; glucose metabolism; glucose tolerance; glycemic control; gut bacteria; gut microbiome; gut microbiota; gut-liver axis; hormone regulation; ileum; improved; in vivo; insulin tolerance; lipid metabolism; liver inflammation; liver metabolism; male; microbial; microbiome; microbiome analysis; non-alcoholic fatty liver disease; novel; overexpression; oxysterol 7-alpha-hydroxylase; promoter; response; time use; transcriptome sequencing; western diet

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.

2 型糖尿病和肥胖与血脂异常、高血糖和胰岛素抵抗有关。肝的 脂肪变性导致胰岛素抵抗和非酒精性脂肪肝。胆汁酸起着关键作用 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 TGR5。我们的中心假设是营养素、生长激素、昼夜节律 肠道微生物群调节胆汁酸合成以维持代谢稳态，以及代谢稳态的损害 调节反应导致血脂异常、葡萄糖耐受不良、胰岛素抵抗、脂肪肝疾病 和肥胖。具体目标1将研究胆汁酸受体信号传导在肝脏调节中的作用 代谢。生长激素-STAT5调节胆汁酸合成的机制及男性 将使用报告基因测定和染色质免疫沉淀测定来研究主要的 Cyp7b1 鉴定 STAT5 结合位点以及 STAT5 对 Cyp7b1 启动子的表观遗传调控。 Tgr5-/-、Cyp7a1-/- 腺病毒-Cyp8b1过表达具有不同胆汁酸组成和Cyp7a1、Cyp8b1和 cyp7b1 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受体信号传导。 FXR和TGR5的作用机制 将研究 GLP-1 分泌和葡萄糖代谢。 Tgr5-/- 小鼠将用于研究垂直方向的影响 袖状胃切除术对术前和术后改善胰岛素抵抗、血脂异常和微生物组的影响。 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至关重要的作用，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。 Tgr5-/-、FXR-/- 具有不同胆汁酸库大小和/或组成的 Cyp7a1-/- 将用于限时饲喂 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。 Cyp7a1-/-、Fxr-/- 和 Tgr5-/- 将用于确定白天如何进行时间限制喂养 或夜间影响会影响肝脏基因节律和整体胆汁酸稳态。