Identification of Novel Genes/Pathways That Regulate Lipid and Glucose Metabolism

调节脂质和葡萄糖代谢的新基因/途径的鉴定

• 批准号: 8345198
• 负责人: Yanqiao Zhang
• 金额: $ 30.75万
• 依托单位: NORTHEAST OHIO MEDICAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-15 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8345198
• 关键词: Adipose tissue; Adult; Affect; Atherosclerosis; Bile Acids; Biochemical; Blood Glucose; Carboxylic Ester Hydrolases; Cholesterol; Cholesterol Esters; Cirrhosis; Data; Development; Dyslipidemias; Fatty Liver; Fibrosis; Genes; Glucose; Goals; Health; Hepatic; Hepatocyte; Homeostasis; Human; Hydrolase; Hydrolysis; Inflammatory; Insulin Resistance; Lead; Ligands; Lipase; Lipids; Liver; Liver diseases; Metabolic Pathway; Metabolic syndrome; Molecular; Mus; Non-Insulin-Dependent Diabetes Mellitus; Nuclear Hormone Receptors; Nuclear Receptors; Obesity; Pathway interactions; Peripheral; Physiology; Plasma; Play; Rattus; Receptor Signaling; Risk Factors; Role; Testing; Triglyceride Metabolism; Triglycerides; activating transcription factor; base; blood glucose regulation; carbohydrate metabolism; carboxylesterase; design; esterase; glucose metabolism; glucose tolerance; human carboxylesterase 1; improved; in vivo; insight; insulin sensitivity; lipid metabolism; member; non-alcoholic fatty liver; nonalcoholic steatohepatitis; novel; prevent; receptor; reverse cholesterol transport; therapeutic target

DESCRIPTION (provided by applicant): Non-alcoholic fatty liver (NAFLD) refers to a wide spectrum of liver disorders ranging from hepatic steatosis to nonalcoholic steatohepatitis, fibrosis and cirrhosis. NAFLD is often associated with obesity, insulin resistance, type 2 diabetes and dyslipidemia. Farnesoid X receptor (FXR) is a nuclear hormone receptor and plays an important role in maintaining bile acid, lipid and glucose homeostasis. Our long-term goal is to identify novel genes/pathways that regulate lipid and carbohydrate metabolism and to elucidate the underlying mechanism(s). Activation of FXR has been shown to lower both hepatic and plasma triglyceride levels. While the mechanism by which FXR regulates plasma triglyceride levels is well understood, the mechanism whereby activation of FXR lowers hepatic triglyceride levels remains to be elucidated. Recent data have suggested that FXR is a therapeutic target for treatment of NAFLD. Thus, elucidation of the mechanism by which activation of FXR lowers hepatic triglyceride levels is both important and necessary. Carboxylesterase 1 (CES1) is highly and principally expressed in the liver. Our preliminary data have shown that i) high blood glucose levels induce hepatic CES1 expression, ii) over-expression of hepatic CES1 markedly reduces hepatic triglyceride levels, lowers plasma glucose levels, and improves glucose tolerance, iii) loss of hepatic CES1 significantly increases hepatic triglyceride levels, and iv) activation of FXR highly induces hepatic CES1 expression. These preliminary data are quite exciting, as they provide the first in vivo evidence that hepatic CES1 may play an important role in regulating hepatic triglyceride and glucose homeostasis. In this proposal, we will further determine the role of hepatic CES1 in controlling glucose and hepatic triglyceride homeostasis and in FXR signaling. We will utilize genetically modified mice, in combination with biochemical, molecular and cellular, and pharmacological approaches to finish the proposed studies. Accomplishing the specific aims in this proposal will provide important insights into the mechanism by which FXR regulates hepatic triglyceride levels, and may identify a novel CES1-glucose-Ces1 pathway that regulates plasma glucose levels. Finally, completion of the proposed studies may lead to identification of hepatic CES1 as a therapeutic target for treatment of NAFLD. PUBLIC HEALTH RELEVANCE: Non-alcoholic fatty liver disease (NAFLD) is one of the most common liver diseases in humans. Completion of the proposed studies will help determine how FXR regulates hepatic triglyceride metabolism and whether hepatic carboxylesterase 1 is a potential target for treatment of NAFLD. Thus, the studies proposed in this application are highly relevant to fatty liver disease and human health.

描述（由申请人提供）：非酒精性脂肪肝（NAFLD）是指广泛的肝脏疾病，范围从肝脂肪变性到非酒精性脂肪性肝炎、纤维化和肝硬化。非酒精性脂肪肝通常与肥胖、胰岛素抵抗、2型糖尿病和血脂异常有关。法尼酯X受体（FXR）是一种核激素受体，在维持胆汁酸、脂质和葡萄糖的稳态中起重要作用。我们的长期目标是鉴定调节脂质和碳水化合物代谢的新基因/途径，并阐明其潜在机制。FXR的激活已被证明可以降低肝脏和血浆甘油三酯水平。虽然FXR调节血浆甘油三酯水平的机制已被充分理解，但FXR活化降低肝脏甘油三酯水平的机制仍有待阐明。最近的数据表明，FXR是治疗NAFLD的治疗靶点。因此，阐明FXR激活降低肝脏甘油三酯水平的机制是重要和必要的。羧酸酯酶1（CES 1）主要在肝脏中高度表达。我们的初步数据表明，i）高血糖水平诱导肝脏CES 1表达，ii）肝脏CES 1的过度表达显着降低肝脏甘油三酯水平，降低血糖水平，并改善葡萄糖耐量，iii）肝脏CES 1的丧失显着增加肝脏甘油三酯水平，和iv）FXR的激活高度诱导肝脏CES 1表达。这些初步数据是非常令人兴奋的，因为它们提供了第一个体内证据，表明肝脏CES 1可能在调节肝脏甘油三酯和葡萄糖稳态中发挥重要作用。在这个提议中，我们将进一步确定肝脏CES 1在控制葡萄糖和肝脏甘油三酯稳态以及FXR信号传导中的作用。我们将利用转基因小鼠，结合生物化学、分子和细胞以及药理学方法来完成拟议的研究。实现本提案中的具体目标将为FXR调节肝脏甘油三酯水平的机制提供重要见解，并可能确定一种调节血糖水平的新型CES 1-葡萄糖-Ces 1途径。最后，完成拟议的研究可能会导致确定肝CES 1作为治疗NAFLD的治疗靶点。 公共卫生相关性：非酒精性脂肪肝（NAFLD）是人类最常见的肝脏疾病之一。完成拟议的研究将有助于确定FXR如何调节肝脏甘油三酯代谢以及肝脏羧酸酯酶1是否是治疗NAFLD的潜在靶点。因此，本申请中提出的研究与脂肪肝疾病和人类健康高度相关。