IGFBP-1-Integrin-FAK轴调控胰岛素敏感性及其在脂肪肝发病中的作用和机制研究

胰岛素抵抗是非酒精性脂肪性肝病（NAFLD）发病机制中的重要环节，我们前期研究发现，NAFLD中粘着斑激酶（FAK）激活受到抑制，胰岛素样生长因子结合蛋白-1（IGFBP-1）调控胰岛素敏感性，其在NAFLD中作用尚不清楚，我们推测其Arg-Gly-Asp(RGD)区域与整合素(integrin)结合，通过IGFBP-1-Integrin-FAK轴调控胰岛素敏感性，参与NAFLD发病机制。本研究拟建立NAFLD细胞和小鼠模型，检测IGFBP-1-Integrin-FAK轴的表达水平；在体外和体内两个水平，采用干扰或过表达技术抑制或增强IGFBP-1和/或整合素β1表达，改变FAK磷酸化水平，检测肝糖原合成和糖异生的变化，观察胰岛素敏感性及其对肝细胞脂变的影响。本研究的实施将阐明IGFBP-1-Integrin-FAK轴在NAFLD中的作用和调控分子机制，为发现潜在的药物靶标奠定基础。

Insulin resistance plays an important pole in the pathogenesis of non-alcoholic fatty liver disease (NAFLD), Our previous study found focal adhesion kinase (FAK) activation was inhibited in NAFLD,insulin-like growth factor binding protein-1 (IGFBP-1) regulates insulin sensitivity, while its role in NAFLD is unclear, we infer its Arg-Gly-Asp (RGD) area may combine with integrin，and IGFBP-1-Integrin-FAK axis could control insulin sensitivity and take parcipate in the NAFLD pathogenesis. In this study, we intend to establish the NAFLD-cell model and mouse model to test IGFBP-1-Integrin-FAK axis levels. From two levels of in vitro and in vivo, we use RNA interference or overexpression technology to inhibite or increase IGFBP-1 and / or β1 integrin expression, and change phosphorylated FAK expression levels, test hepatic glycogensynthesis and gluconeogenesis changes to obeserve insulin sensitivity, and test steatosis of liver cells. We will clarify IGFBP-1-Integrin-FAK axis's role in NAFLD and regulation molecular mechanism through this study and lay the foundation for a potential drug target.