HGF/HGFR Axis and Fatty Liver Disease

大约四分之一的美国公民有脂肪变性或脂肪积聚在肝细胞中。根本原因 脂肪肝(FL)的发病率很高，但饮酒和肥胖是最常见的。肥胖和FL是 与代谢综合征(MetSyn)有关，它包括一系列症状，表明 身体已经对激素胰岛素的新陈代谢作用产生了抵抗力。发展为胰岛素抵抗 肥胖导致的肝脏疾病称为非酒精性脂肪性肝病(NAFLD)， 以肝脏不能抑制葡萄糖合成、不能适当合成和输出葡萄糖为特征的 脂类。非酒精性脂肪肝可导致部分患者出现肝纤维化、肝硬变和肝癌。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的生长有交叉作用 因子受体(HGFR)酪氨酸激酶(又称Met)通过分子间酪氨酸磷酸化。 我们观察到蛋氨酸和IR在肝脏中相互作用，它们的直接联系对适当的胰岛素至关重要 回应。我们的数据使我们认为，在没有Met活性的情况下，IR信号是“迟缓的” 显示信号输出减少。将这一概念进一步发展，我们假设胰岛素 肝脏中的抗性至少部分是由于HGF/Met轴上的信号受损造成的。我们建议两个 全面、具体的目标是检验这些想法。在目标1中，我们将分析分子间的相互作用， Met和IR的激活和信号转导。在目标2中，我们将检查Met和IR的后果 肝细胞内分子间相互作用及其对肝糖和肝细胞功能的联合贡献 利用细胞培养和转基因小鼠模型相结合的方法研究脂肪酸代谢。我们预料到 从这些实验中获得的数据将引导我们描述胰岛素信号的新范式 转导。通过药物手段增强Met-IR串扰有可能改善胰岛素 对NAFLD和MetSyn表型产生的抗药性。

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.