HGF/HGFR Axis and Fatty Liver Disease

HGF/HGFR 轴与脂肪肝疾病

• 批准号: 8100508
• 负责人: Reza Zarnegar
• 金额: $ 34.24万
• 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/8100508
• 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; glucose metabolism; 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; 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的肝细胞存在脂肪变性或脂肪堆积。脂肪肝 (FL) 的根本原因有很多，但酒精摄入和肥胖是最常见的。肥胖和 FL 与代谢综合征 (MetSyn) 相关，代谢综合征包含一系列症状，表明身体对胰岛素激素的代谢作用产生了抵抗力。由于肥胖而在肝脏中产生的胰岛素抵抗被称为非酒精性脂肪肝病 (NAFLD)，其特征是肝脏无法抑制葡萄糖合成以及适当合成和输出脂质。 NAFLD 会导致一些患者出现肝纤维化、肝硬化和肝癌。我们的新初步数据表明，在肝细胞中，胰岛素受体 (IR) 酪氨酸激酶通过分子间酪氨酸磷酸化与肝细胞生长因子受体 (HGFR) 酪氨酸激酶（也称为 Met）进行串扰。我们观察到 Met 和 IR 在肝脏中相互作用，它们的直接关联对于适当的胰岛素反应至关重要。我们的数据表明，在没有 Met 活性的情况下，IR 信号传导“缓慢”，显示信号输出减少。将这一概念更进一步，我们假设肝脏中的胰岛素抵抗至少部分是由于 HGF/Met 轴信号传导受损造成的。我们提出了两个全面的具体目标来检验这些想法。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，我们将研究肝细胞中 Met 和 IR 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评估它们对肝葡萄糖和脂肪酸代谢的综合贡献。我们预计从此类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例。通过药理学手段增强 Met-IR 串扰可能会改善胰岛素抵抗，而胰岛素抵抗对 NAFLD 和 MetSyn 表型至关重要。公共卫生相关性：脂肪肝 (FL) 是一种严重的健康问题，影响着大约四分之一的美国成年人。 FL 可能导致肝衰竭、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、代谢综合征以及过量饮酒的结果。患有 FL 的人通常对胰岛素激素没有反应。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加敏感，从而减少 FL 的影响。