HGF/HGFR Axis and Fatty Liver Disease

HGF/HGFR 轴与脂肪肝疾病

• 批准号: 8299645
• 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/8299645
• 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

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.

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。根本原因 脂肪肝（FL）的病因很多，但饮酒和肥胖是最常见的。肥胖和FL是 与代谢综合征（MetSyn）相关，其包括一系列症状，表明 身体对胰岛素的代谢作用产生了抵抗力。胰岛素抵抗的发展 肥胖导致的肝脏脂肪肝被称为非酒精性脂肪肝（NAFLD），并且 其特征在于肝脏不能抑制葡萄糖的合成， 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。 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至关重要 反应我们的数据表明，在没有Met活性的情况下，IR信号传导是“缓慢的”。 显示出减小的信号输出。将这一概念再进一步，我们假设胰岛素 肝脏中的抗性至少部分地由HGF/Met轴中受损的信号传导引起。我们提出了两 全面的具体目标，以测试这些想法。在目标1中，我们将分析分子间相互作用， 在目标2中，我们将研究Met和IR的后果 肝细胞中的分子间相互作用，并评估其对肝葡萄糖和 利用细胞培养和转基因小鼠模型的组合进行脂肪酸代谢。我们预计 从这些实验中得到的数据将引导我们描述胰岛素信号的新范例 转导通过药理学手段增强Met-IR串扰可能会改善胰岛素 对NAFLD和MetSyn表型具有重要的耐药性。