HGF/HGFR Axis and Fatty Liver Disease

HGF/HGFR 轴与脂肪肝疾病

基本信息

批准号：
8485464
负责人：
Reza Zarnegar
金额：
$ 31.84万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-01 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8485464
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

项目摘要

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的肝细胞存在脂肪变性或脂肪堆积。根本原因脂肪肝 (FL) 的原因有很多，但酒精摄入和肥胖是最常见的。肥胖和 FL 是与代谢综合症 (MetSyn) 相关，其中包括一系列症状，表明身体对胰岛素激素的代谢作用产生了抵抗力。出现胰岛素抵抗肥胖导致的肝脏疾病称为非酒精性脂肪肝（NAFLD），其特点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）酪氨酸激酶与肝细胞生长相互作用因子受体 (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，它们的直接关联对于适当的胰岛素至关重要回复。我们的数据表明，在缺乏 Met 活性的情况下，IR 信号传导“缓慢” 显示信号输出减少。将这个概念更进一步，我们假设胰岛素肝脏的抵抗至少部分是由于 HGF/Met 轴信号传导受损造成的。我们建议两个综合具体目标来检验这些想法。在目标 1 中，我们将分析分子间相互作用， Met 和 IR 的激活和信号传导。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它们对肝葡萄糖和肝细胞的综合贡献利用细胞培养和转基因小鼠模型的组合进行脂肪酸代谢。我们预计从此类实验中获得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水平耐药性对 NAFLD 和 MetSyn 表型具有重要影响。