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Regulation of Bile Acid Synthesis by Nuclear Receptors

核受体对胆汁酸合成的调节

基本信息

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
项目类别：
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

项目摘要

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(申请人提供)：II型糖尿病和肥胖症与血脂异常、高血糖和胰岛素抵抗有关。肝脏脂肪变性直接导致胰岛素抵抗和非酒精性脂肪肝(NAFLD)。最近的研究表明，胆汁酸不仅是促进类固醇、营养素、维生素、代谢物和外源物质吸收、运输、分配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、糖和能量代谢中发挥关键作用。胆汁酸合成的改变破坏代谢平衡，导致糖尿病、肥胖症和心血管疾病。细胞色素P7A1是肝脏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，抑制CYP7A1基因转录。在肠道中，胆汁酸诱导成纤维细胞生长因子15(FGF15，或人FGF19)，激活肝脏成纤维细胞生长因子受体4信号，抑制细胞色素P7A1。胆汁酸被认为可以降低血清甘油三酯水平，并在维持糖脂平衡方面发挥关键作用，然而，其潜在的机制尚不清楚。我们的中心假设是，CYP7A1的表达和胆汁酸的合成受到营养状况的高度调控，以维持糖和脂的平衡，并防止饮食诱导的肝脏脂肪变性、肥胖和胰岛素抵抗。具体目标1将研究CYP7A1在胆汁酸合成和肝脏代谢稳态中的营养调节。我们将研究葡萄糖和胰岛素诱导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CYP7A1表达的机制。具体目标2将研究CYP7A1在脂肪肝、糖尿病和肥胖症中的作用。我们已经证明，在小鼠(Cyp7a1转基因小鼠)中转基因表达Cyp7a1可以保护小鼠免受饮食诱导的肝脏脂肪变性、胰岛素抵抗和肥胖的影响。我们将使用缺乏CYP7A1(Cyp7a1-/-)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。我们还将把Cyp7a1转基因小鼠与FXR-/-小鼠交叉，以测试增加的疏水胆汁酸信号是否足以纠正胰岛素抵抗。具体目标3将使用人源化的CYP7A1小鼠模型来研究体内人类CYP7A1基因的调控。这项研究将为人类胆汁酸合成调控的分子机制提供进一步的认识。这种人源化的小鼠模型将用于研究饮食诱导的肥胖和胰岛素抵抗，并可能用于筛选治疗NAFLD、糖尿病和肥胖症的治疗药物。本研究的长期目标是阐明细胞色素P7A1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。