胰岛素抵抗和Foxo信号对肝纤维化的调控

项目名称： 胰岛素抵抗和Foxo信号对肝纤维化的调控

项目编号： No.81471022

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 齐亚娟

作者单位： 华北理工大学

项目金额： 73万元

中文摘要： 胰岛素抵抗是2型糖尿病的重要标志,其所诱发的肝纤维化近年来迅速增加，而肝纤维化是肝功能衰竭的常见原因。胰岛素通过激活MAPK和PI3K两条信号通路促进细胞生长、代谢和存活，转录因子Foxo1是PI3K信号途径的关键靶分子。我们证实，糖尿病小鼠肝脏胰岛素→PI3K→Akt的激活被阻断，Foxo1基因被激活，肝脏出现纤维化和衰竭，而肝脏敲除Foxo1基因，可减轻肝纤维化，但机制尚不清楚。已知肝纤维化涉及肝星状细胞（HSC）和TGF-β1的激活，Smad4介导的基因转录和细胞外基质表达增加。我们发现在TGF-β1启动子区含有Foxo1结合位点。因此，本课题设想胰岛素抵抗时，肝脏Foxo1基因被激活，促进TGF-β1表达和分泌，继而激活HSC对纤维化物质的分泌，抑制肝细胞增殖，诱导肝纤维化、细胞凋亡和肝脏衰竭，为胰岛素抵抗调控肝纤维化提供新的分子机制。

中文关键词： 胰岛素抵抗；2型糖尿病；胰岛素信号转导

英文摘要： Insulin resistance is a hallmark of type 2 diabetes mellitus.Recently,hepatic fibrosis caused by insulin resistance increased dramatically.Liver fibrosis is a common cause of liver failure.Insulin promotes cellular growth, metabolism and survival by activating both mitogen-activated protein (MAP) kinase and phosphatidylinositol 3'-kinase (PI3K) signaling cascades. We demonstrated that in the liver of diabetic mice, PI3K→Akt activation by insulin is blocked, resulting in Foxo1 activation and hepatic fibrosis and liver failure. Moreover，hepatic Foxo1 deficiency improves hepatic fibrosis and blocks liver failure in mice with type 2 diabetes mellitus. However, the mechanism is unclear. Liver fibrosis involved in activating hepatic stellate cells (HSC) and TGF-β1 promoting Smad4-mediated gene transcription and extracellular matrix gene expression. We found that the TGF-β1 promoter region contains a Foxo1 binding site. Thus, we hypothesize that Foxo1 activation in hepatocytes promotes expression and secretion of TGF-β1, a cytokine that activates hepatic stellate cells (HSC) for fibrogenesis, while inhibiting hepatocyte proliferation to induce hepatic fibrosis, apoptosis and failure following insulin resistance. These will provide new molecular mechanisms for the control of liver fibrosis by insulin resistance.

英文关键词： insulin resistance;type 2 diabetes;insulin signaling pathway