HGF/HGFR Axis and Fatty Liver Disease

HGF/HGFR 轴与脂肪肝疾病

• 批准号: 7632727
• 负责人: Reza Zarnegar
• 金额: $ 35.98万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7632727
• 关键词: Adult; Affect; Alcohol abuse; Alcohol consumption; Alcohols; American; Biological; Biological Assay; Cell Culture Techniques; Cell Line; Cells; Cessation of life; Cirrhosis; Complement; Complex; Data; Disease; Docking; Fatty Liver; Fatty acid glycerol esters; Glucose; Health; Hepatic; Hepatocyte; Hormones; Hybrids; Ingestion; Insulin; Insulin Receptor; Insulin Resistance; Lead; Life; Lipids; Liver; Liver Failure; Liver Fibrosis; Liver diseases; Malignant neoplasm of liver; Metabolic; Metabolic syndrome; Mus; Nutritional; Obesity; Output; Overweight; Patients; Persons; Pharmaceutical Preparations; Phenotype; Phosphotransferases; Protein Tyrosine Kinase; Proteins; Proto-Oncogene Protein c-met; Receptor Signaling; Recombinants; Resistance; Seminal; Series; Signal Transduction; Site; Symptoms; Testing; Tissues; Toxin; Transgenic Mice; Transplantation; Triglycerides; Tyrosine; Tyrosine Phosphorylation; base; fatty acid metabolism; glucose disposal; improved; insulin receptor serine kinase; insulin receptor tyrosine kinase; insulin signaling; intermolecular interaction; lipid metabolism; meetings; mouse model; mutant; non-alcoholic fatty liver; protein expression; public health relevance; research study; response

DESCRIPTION (provided by applicant): Roughly a quarter of U.S. citizens have steatosis or fat accumulation in their liver cells. The underlying causes of fatty liver (FL) are numerous, but alcohol intake and obesity rank as the most common. Obesity and FL are associated with Metabolic Syndrome (MetSyn) which encompasses a constellation of symptoms indicating that the body has become resistant to the metabolic effects of the hormone insulin. Insulin resistance that develops in the liver as a consequence of obesity is known as non-alcoholic fatty liver disease (NAFLD) and is characterized by the liver's inability to suppress glucose synthesis and to appropriately synthesize and export lipids. NAFLD leads to hepatic fibrosis, cirrhosis and liver cancer in some patients. Our new preliminary data indicate that, in hepatocytes, the insulin receptor (IR) tyrosine kinase crosstalks with the Hepatocyte Growth Factor Receptor (HGFR) tyrosine kinase (also known as Met) through intermolecular tyrosine phosphorylation. We observe that Met and IR interact in the liver and that their direct association is crucial to a proper insulin response. Our data have led us to suggest that, in the absence of Met activity, IR signaling is `sluggish' showing reduced signal output. Taking this concept another step further, we hypothesize that insulin resistance in the liver results at least in part from impaired signaling in the HGF/Met axis. We propose two comprehensive specific aims to test these ideas. In Aim 1, we will analyze the intermolecular interaction, activation and signaling of Met and IR. In Aim 2, we will examine the consequences of Met and IR intermolecular interaction in hepatocytic cells and evaluate their combined contribution to hepatic glucose and fatty acid metabolism utilizing a combination of cell culture and transgenic mouse models. We anticipate that data derived from these kinds of experiments will lead us to describe a new paradigm in insulin signal transduction. It is possible that enhancing Met-IR crosstalk through pharmacologic means will improve insulin resistance which is seminal to the NAFLD and MetSyn phenotype. PUBLIC HEALTH RELEVANCE: Fatty liver (FL) is serious health concern affecting about one quarter of adult Americans. FL may cause liver failure, cirrhosis and death. To save a person's life with FL, their liver may need to be transplanted. Fatty liver can be the result of being overweight, having metabolic syndrome as well as consuming too much alcohol. People suffering from FL often do not respond to the hormone insulin. Our studies show that a protein known as Met which interacts with the insulin receptor may be a culprit underlying the liver's inability to respond to insulin. We will study the interaction of Met and insulin receptor to figure out how to make livers more responsive to insulin to reduce the effects of FL.

描述（由申请人提供）：大约四分之一的美国公民在他们的肝细胞中有脂肪变性或脂肪堆积。脂肪肝（FL）的潜在原因很多，但酒精摄入和肥胖是最常见的。肥胖和FL与代谢综合征（MetSyn）有关，代谢综合征包括一系列症状，表明身体对激素胰岛素的代谢作用产生了抵抗。由于肥胖而在肝脏中发展的胰岛素抵抗被称为非酒精性脂肪肝病（NAFLD），其特征在于肝脏不能抑制葡萄糖合成以及不能适当地合成和输出脂质。NAFLD在一些患者中导致肝纤维化、肝硬化和肝癌。我们新的初步数据表明，在肝细胞中，胰岛素受体（IR）酪氨酸激酶与肝细胞生长因子受体（HGFR）酪氨酸激酶（也称为Met）通过分子间酪氨酸磷酸化发生交联。我们观察到Met和IR在肝脏中相互作用，并且它们的直接关联对于适当的胰岛素反应至关重要。我们的数据已经使我们表明，在Met活性的情况下，IR信号传导是“迟缓的”，显示出减少的信号输出。进一步考虑这一概念，我们假设肝脏中的胰岛素抵抗至少部分来自HGF/Met轴中受损的信号传导。我们提出了两个全面的具体目标来测试这些想法。在目标1中，我们将分析Met和IR的分子间相互作用、激活和信号传导。在目标2中，我们将研究Met和IR在肝细胞中的分子间相互作用的后果，并利用细胞培养和转基因小鼠模型的组合来评估它们对肝脏葡萄糖和脂肪酸代谢的联合贡献。我们预计，从这些实验中获得的数据将引导我们描述胰岛素信号转导的新范式。通过药理学手段增强Met-IR串扰可能会改善胰岛素抵抗，这对NAFLD和MetSyn表型至关重要。脂肪肝（FL）是一种严重的健康问题，影响大约四分之一的美国成年人。FL可导致肝衰竭、肝硬化和死亡。为了挽救FL患者的生命，他们的肝脏可能需要移植。脂肪肝可能是超重的结果，有代谢综合征以及消耗过多的酒精。患有FL的人通常对激素胰岛素没有反应。我们的研究表明，一种名为Met的蛋白质与胰岛素受体相互作用，可能是导致肝脏无法对胰岛素做出反应的罪魁祸首。我们将研究Met和胰岛素受体的相互作用，以找出如何使肝脏对胰岛素更敏感，以减少FL的影响。