Role of GDNF in the regulation of hepatic steatosis

GDNF在肝脂肪变性调节中的作用

• 批准号: 8440394
• 负责人: Shanthi K Srinivasan
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-10-01 至 2016-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8440394
• 关键词: Biogenesis; CD36 gene; Cell Line; Centers for Disease Control and Prevention (U.S.); Data; Development; Diabetes Mellitus; Diet; Down-Regulation; Eating; Encapsulated; Energy Metabolism; Enteric Nervous System; Enzymes; Epidemic; FASN gene; FDA approved; Fasting; Fatty Acids; Fatty Liver; Fatty acid glycerol esters; Fluorescein-5-isothiocyanate; Functional disorder; Gastrointestinal Motility; Genes; Glial Fibrillary Acidic Protein; Glucose; Glucose tolerance test; Goals; Health; Health Care Costs; Healthcare; Healthcare Systems; Hepatic; Hepatocyte; Human; In Vitro; Incidence; Indirect Calorimetry; Injection of therapeutic agent; Intraperitoneal Injections; Kidney; Laboratories; Lead; Lipids; Liver; Liver diseases; Lung; Metabolic syndrome; Metabolism; Mitochondria; Molecular; Mus; Neuroglia; Obesity; Obesity associated liver disease; Organ; Outcome; Overweight; Patients; Peroxisome Proliferator-Activated Receptors; Pharmaceutical Preparations; Physical activity; Platelet Factor 4; Play; Population; Prevalence; Prevention; Process; Recombinants; Regulation; Reporting; Role; Serum; Signal Pathway; Signal Transduction Pathway; Testing; Transgenic Mice; Treatment Efficacy; Triglycerides; Up-Regulation; Veterans; Weight; Weight Gain; base; chronic liver disease; cost; fatty acid oxidation; feeding; improved; in vivo; knock-down; lipid biosynthesis; motility disorder; nanoparticle; neurotrophic factor; new therapeutic target; non-alcoholic fatty liver; novel; oxidation; prevent; promoter; public health relevance; receptor; research study

DESCRIPTION (provided by applicant): Non-alcoholic fatty liver disease (NAFLD) is a common cause of chronic liver disease in Veterans and its prevalence continues to increase, with the growing obesity epidemic. Hepatic steatosis is a component of NAFLD, wherein there is accumulation of triglycerides in the liver. Recently we discovered that (i) GDNF transgenic mice when fed a high fat diet resist weight gain and development of hepatic steatosis, despite similar food intake and physical activity. GDNF transgenic mice over express GDNF in glia under the GFAP promoter (GDNF-tg) (ii) GDNF (expressed in glia) and its receptor GFR-1a are expressed in human and murine hepatocytes (iii) GDNF-tg mice demonstrate enhanced energy utilization assessed by indirect calorimetry, (iv) compared to WT mice fed a high fat diet the GDNF-tg mice have lower serum glucose levels and improved glucose tolerance tests. The mechanisms for these potentially beneficial effects of GDNF have yet to be explored. We hypothesize that the mechanism of GDNF prevention of high fat diet induced hepatic steatosis is through improved hepatic energy expenditure and inhibition of hepatic lipogenesis. In this proposal we will establish the necessity and sufficiency of GDNF in regulating hepatic steatosis. Currently there are few FDA approved drugs for the treatment of hepatic steatosis. We have identified a novel role for the neurotrophic factor, GDNF, that improves fatty acid b-oxidation with a combined reduction in lipogenesis; an outcome that has not been previously achieved. We will examine the mechanism underlying these processes utilizing in vitro and in vivo approaches involving over expression or knock down of its receptor GFRa1 and dissect the signaling pathways involved. In Specific Aim 1 we will determine the role of GDNF in enhancing fatty acid beta oxidation in hepatocytes. Preliminary data suggests that GDNF can activate Peroxisome proliferator- activated receptor coactivator -1a (PGC-1a) in hepatocytes, resulting in up regulation of enzymes related to fatty acids beta-oxidation and mitochondrial biogenesis. We will establish the necessity and sufficiency of GDNF in regulating hepatic fatty acid oxidation using mice over expressing GDNF (GDNF-tg mice) in vivo and in hepatocytes in vitro. In Specific Aim 2 we will demonstrate the molecular basis of GDNF inhibition of hepatic lipogenesis, focusing on GDNF downregulation of PPAR-g and its downstream lipogenic genes, FASN and CD36. Our preliminary results indicate GDNF results in a reduced expression of PPAR-g. In Specific Aim 3 we will deliver hepatocytes-specific GDNF-encapsulated nanoparticles to the liver for targeted therapy of hepatic steatosis to HF-diet fed mice and assess the therapeutic efficacy of GDNF to prevent or treat HF-diet induced steatosis in mice. Impact on Veterans Health Care: Currently more than 25% of our Veterans are obese and a larger number are overweight. In 2008, complications arising from obesity and its related metabolic syndrome cost the US health care system $147 billion (CDC MMWR report, August 2010). Strategies to prevent and treat obesity can reduce obesity related complications (like NAFLD) and health care costs. Identification of new therapies for hepatic steatosis will directly benefit the veteran population. Taken together our data from this proposal may provide novel targets for the treatment or prevention of hepatic steatosis.

描述（由申请人提供）： 非酒精性脂肪性肝病（NAFLD）是退伍军人慢性肝病的常见原因，其患病率随着肥胖流行病的日益严重而持续增加。肝脂肪变性是NAFLD的一个组成部分，其中在肝脏中存在甘油三酯的积累。最近我们发现（i）GDNF转基因小鼠在喂食高脂肪饮食时抵抗体重增加和肝脂肪变性的发展，尽管相似的食物摄入和体力活动。GDNF转基因小鼠在GFAP启动子（GDNF-tg）下在神经胶质中过表达GDNF（ii）GDNF（在神经胶质中表达）及其受体GFR-1a在人和鼠肝细胞中表达（iii）GDNF-tg小鼠通过间接量热法评估显示增强的能量利用，（iv）与喂食高脂肪饮食的WT小鼠相比，GDNF-tg小鼠具有较低的血清葡萄糖水平和改善的葡萄糖耐量试验。GDNF的这些潜在有益作用的机制还有待探索。我们推测GDNF预防高脂饮食诱导的肝脂肪变性的机制是通过改善肝脏能量消耗和抑制肝脏脂肪生成。在本提案中，我们将确定 GDNF在调节肝脂肪变性中的作用。目前，很少有FDA批准的用于治疗肝脂肪变性的药物。我们已经确定了神经营养因子GDNF的一个新的作用，它可以改善脂肪酸b-氧化，同时减少脂肪生成;这是以前没有实现的结果。我们将研究这些过程的机制，利用在体外和体内的方法，涉及过表达或敲低其受体GFRa 1和解剖的信号通路。在具体目标1中，我们将确定GDNF在增强肝细胞中脂肪酸β氧化中的作用。初步数据表明，GDNF可以激活肝细胞中的过氧化物酶体增殖物激活受体辅激活因子-1a（PGC-1a），导致与 脂肪酸β-氧化和线粒体生物合成。我们将在体内和体外使用过表达GDNF的小鼠（GDNF-tg小鼠）在肝细胞中建立GDNF调节肝脂肪酸氧化的必要性和充分性。在《特定目标2》中，我们将证明GDNF抑制肝脏脂肪生成的分子基础，重点关注GDNF下调PPAR-g及其下游脂肪生成基因FASN和CD 36。我们的初步结果表明GDNF导致PPAR-g的表达减少。在具体目标3中，我们将向肝脏递送肝细胞特异性GDNF包封的纳米颗粒，用于HF饮食喂养的小鼠的肝脂肪变性的靶向治疗，并评估GDNF预防或治疗HF饮食诱导的小鼠脂肪变性的治疗功效。对退伍军人医疗保健的影响：目前超过25%的退伍军人肥胖，更多的人超重。2008年，肥胖及其相关代谢综合征引起的并发症花费了美国医疗保健系统1470亿美元（CDC MMWR报告，2010年8月）。预防和治疗肥胖的策略可以减少肥胖相关的并发症（如NAFLD）和医疗保健费用。确定新的治疗肝脂肪变性的方法将直接受益于退伍军人群体。总之，我们的数据从这个建议可能提供新的目标，治疗或预防肝脂肪变性。