Regulation of Bile Acid Synthesis by Nuclear Receptors

核受体对胆汁酸合成的调节

• 批准号: 8454527
• 负责人: JOHN Y. L. CHIANG
• 金额: $ 32.32万
• 依托单位: NORTHEAST OHIO MEDICAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-08-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8454527
• 关键词: Adult; Affect; Bile Acid Biosynthesis Pathway; Bile Acids; Biological Assay; CYP7A1 gene; Cardiovascular Diseases; Cholesterol 7-alpha-Monooxygenase; Detergents; Diabetes Mellitus; Diabetes prevention; Diabetic mouse; Diet; Disease; Dyslipidemias; Energy Metabolism; Enzymes; Fasting; Fatty Liver; Fatty acid glycerol esters; Fibroblast Growth Factor; Fibroblast Growth Factor Receptors; Gene Expression Regulation; Genes; Genetic; Genetic Transcription; Glucose; Grant; Hepatic; Hepatocyte; Homeostasis; Human; Hyperglycemia; In Vitro; Inflammatory; Insulin; Insulin Resistance; Intestines; Knowledge; Leptin; Lipids; Liver; Liver diseases; Metabolic; Metabolic Control; Metabolic Diseases; Metabolism; Molecular; Mus; Non-Insulin-Dependent Diabetes Mellitus; Nuclear Receptors; Nutrient; Nutritional status; Obesity; Pathogenesis; Pathway interactions; Pharmaceutical Preparations; Physiological; Physiology; Play; Population; Predisposition; Prevention; Receptor Cell; Regulation; Regulator Genes; Reporting; Research; Research Project Grants; Role; Serum; Signal Pathway; Signal Transduction; Signaling Molecule; Steroids; Sterols; Stimulus; Streptozocin; Testing; Therapeutic; Transcriptional Regulation; Transgenes; Transgenic Mice; Transgenic Organisms; Triglyceride Metabolism; Triglycerides; United States; Vitamins; Wild Type Mouse; Xenobiotics; absorption; blood glucose regulation; design; diabetic; feeding; glucose metabolism; glucose tolerance; improved; in vivo; in vivo Model; insight; insulin sensitivity; lipid metabolism; liver metabolism; mouse model; non-alcoholic fatty liver; novel; obesity prevention; prevent; public health relevance; screening; type I diabetic

DESCRIPTION (provided by applicant): Type II diabetes and obesity are associated with dyslipidemia, hyperglycemia and insulin resistance. Hepatic steatosis directly contributes to insulin resistance and non-alcoholic fatty liver disease (NAFLD). Recent studies have shown that bile acids not only are physiological detergents that facilitate absorption, transport, distribution and disposal of steroids, nutrients, vitamins, metabolites and xenobiotics, but also are signaling molecules that activate nuclear receptors and cell signaling pathways and play critical roles in regulation of lipid, glucose, and energy metabolisms. Alteration of bile acid synthesis impairs metabolic homeostasis leading to diabetes, obesity, and cardiovascular diseases. CYP7A1 is the rate-limiting enzyme of the bile acid biosynthetic pathway in the liver. In the liver, bile acid activates the FXR/SHP pathway to inhibit CYP7A1 gene transcription. In the intestine, bile acids induce a fibroblast growth factor 15 (FGF15, or human FGF19), which activates hepatic FGF receptor 4 signaling to inhibit CYP7A1. Bile acids are known to reduce serum triglyceride levels and play critical role in maintaining glucose and lipid homeostasis, however, the underlying mechanism remains unclear. Our central hypotheses are that CYP7A1 expression and bile acid synthesis are highly regulated by nutritional status to maintain glucose and lipid homeostasis, and to protect against diet-induced hepatic steatosis, obesity and insulin resistance. The Specific Aim 1 will study nutrient regulation of CYP7A1 in bile acid synthesis and liver metabolic homeostasis. We will study the mechanisms of glucose and insulin induction of CYP7A1 expression in wild type mice and streptozotocin- induced type 1 diabetic mice, genetic obese type II diabetic ob/ob mice, and insulin resistance Fxr-/- mice. The Specific Aim 2 will study the role of CYP7A1 in fatty liver, diabetes and obesity. We have shown that transgenic expression of Cyp7a1 in mice (Cyp7a1-transgenic mice) protected mice from diet-induced hepatic steatosis, insulin resistance and obesity. We will use mice deficient of CYP7A1 (Cyp7a1-/-) to study if bile acid deficiency will increase susceptibility to diet-induced obesity and insulin resistance. We will also cross Cyp7a1- transgenic mice to Fxr-/- mice to test if increased hydrophobic bile acid signaling is sufficient for correcting insulin resistance. The Specific Aim 3 will use a humanized CYP7A1 mouse model for studying human CYP7A1 gene regulation in vivo. This study will provide further insight into the molecular mechanism of regulation of bile acid synthesis in humans. This humanized mouse model will be used to study diet-induced obesity and insulin resistance, and may be used for screening therapeutic drugs for treatment of NAFLD, diabetes and obesity. The long-term objectives of this research are to elucidate the molecular mechanism of regulation of CYP7A1 and bile acid metabolism, and pathogenesis and treatment of metabolic diseases such as fatty liver disease, diabetes and obesity.

描述（由申请人提供）：II型糖尿病和肥胖症与血脂异常、高血糖症和胰岛素抵抗相关。肝脏脂肪变性直接导致胰岛素抵抗和非酒精性脂肪性肝病（NAFLD）。近年来的研究表明，胆汁酸不仅是促进类固醇、营养素、维生素、代谢物和外源性物质吸收、转运、分布和处置的生理性洗涤剂，而且是激活核受体和细胞信号通路的信号分子，在调节脂质、葡萄糖和能量代谢中起着关键作用。胆汁酸合成的改变损害代谢稳态，导致糖尿病、肥胖和心血管疾病。CYP 7A 1是肝脏中胆汁酸生物合成途径的限速酶。在肝脏中，胆汁酸激活FXR/SHP途径以抑制CYP 7A 1基因转录。在肠道中，胆汁酸诱导成纤维细胞生长因子15（FGF 15或人FGF 19），其激活肝FGF受体4信号传导以抑制CYP 7A 1。已知胆汁酸可降低血清甘油三酯水平，并在维持血糖和脂质稳态中起关键作用，然而，其潜在机制仍不清楚。我们的中心假设是，CYP 7A 1的表达和胆汁酸的合成高度调节营养状况，以维持葡萄糖和脂质的稳态，并防止饮食诱导的肝脂肪变性，肥胖和胰岛素抵抗。具体目标1将研究CYP 7A 1在胆汁酸合成和肝脏代谢稳态中的营养调控。我们将在野生型小鼠和链脲佐菌素诱导的1型糖尿病小鼠、遗传性肥胖II型糖尿病ob/ob小鼠和胰岛素抵抗Fxr-/-小鼠中研究葡萄糖和胰岛素诱导CYP 7A 1表达的机制。具体目标2将研究CYP 7A 1在脂肪肝、糖尿病和肥胖症中的作用。我们已经证明，Cyp 7a 1在小鼠中的转基因表达（Cyp 7a 1转基因小鼠）保护小鼠免受饮食诱导的肝脂肪变性，胰岛素抵抗和肥胖。我们将使用CYP 7A 1（Cyp 7a 1-/-）缺陷的小鼠来研究胆汁酸缺乏是否会增加饮食诱导的肥胖和胰岛素抵抗的易感性。我们还将Cyp 7a 1转基因小鼠与Fxr-/-小鼠杂交，以测试增加的疏水性胆汁酸信号传导是否足以纠正胰岛素抵抗。具体目标3将使用人源化CYP 7A 1小鼠模型研究体内人CYP 7A 1基因调控。这项研究将提供进一步了解调节胆汁酸合成在人类的分子机制。该人源化小鼠模型将用于研究饮食诱导的肥胖和胰岛素抵抗，并可用于筛选治疗NAFLD、糖尿病和肥胖的治疗药物。本研究的长期目标是阐明CYP 7A 1和胆汁酸代谢调节的分子机制，以及脂肪肝、糖尿病和肥胖等代谢性疾病的发病机制和治疗。