玻连蛋白/整合素avβ5在oxLDL诱导的脂肪肝肝窦功能障碍中的作用机制

氧化型低密度脂蛋白(oxLDL)诱导的肝窦功能障碍是糖尿病合并脂肪肝的重要病理机制。玻连蛋白(VN)与整合素avβ5结合可介导细胞信号转导。我们前期研究表明，oxLDL与LOX-1结合导致肝窦内皮细胞(LSEC)功能障碍伴随LSEC整合素avβ5表达上调，然而avβ5在肝窦功能障中的作用机制不清，国内外未见报道。本研究利用糖尿病脂肪肝小鼠模型，观察肝窦功能障碍中毛细血管化程度和VN、avβ5及LOX-1表达水平；利用基因工程小鼠研究LOX-1 和VN/avβ5是否介导了FAK/Rho GTPase的变化以及肝窦功能障碍与其依赖程度；在细胞水平进一步确认oxLDL引起肝窦功能障碍的分子机制，包括oxLDL对VN、avβ5、LOX-1及FAK/Rho GTPase表达的影响。旨在探讨糖尿病状态下VN/avβ5介导oxLDL诱导脂肪肝肝窦功能障碍的分子机制，为防治糖尿病合并脂肪肝提供理论依据。

oxLDL is one of the risk factors for hepatic sinusiodal dysfunction of diabetic fatty liver disease. Combination of vitronectin (VN) with its receptor intergrin avβ5 mediates the signal transduction. Our previous studies have shown that oxLDL combines with LOX-1 which leads to the change in structure and function of liver sinusoidal endothelial cells (LSEC). In addition, we found that oxLDL increased the expression of avβ5 in LSEC. However, the role of avβ5 in hepatic sinusiodal dysfunction remains unknown. In this study, by using diabetic fatty liver disease mice model, the degree of sinusiod capillarization in hepatic sinusiodal dysfunction and expressions of LOX-1 and avβ5 gene knockout mouse and the modern molecular biological appoaches, we will investigate the mechanisms by which oxLDL in combination with LOX-1 increased the expression of VN/integrin avβ5, activates FAK/Rho GTPase pathway and promotes the occurrence of hepatic sinusiodal dysfunction in hepatic tissue or LSEC at the levels of animal, cell and molecule. The aim of this study is to explore the mechanism of VN/integrin avβ5 mediated fatty liver disease and to provide a theoretical basis for the prevention and treatment of diabetes with fatty liver disease.