靶向PPARγ通路调控巨噬细胞/Kupffer细胞与肝星状细胞交互作用预防NASH肝纤维化机制研究

炎症-纤维化轴的启动和持续激活是NASH发展的重要环节，肝脏巨噬细胞/Kupffer细胞和肝星状细胞（HSC）在炎症-纤维化进程中发挥重要作用。核受体PPARγ在抗炎和抗肝纤维化中显示出潜在的积极作用。我们前期研究发现调控PPARγ表达可促进巨噬细胞/Kupffer细胞M1/M2极化转变，从而阻止或启动高脂诱导的炎症反应。因此，本项目拟通过动物和细胞模型研究NASH发展过程中巨噬细胞/Kupffer细胞和HSC的交互作用在疾病进展中的作用，体内外靶向调控PPARγ表达及活性对两者交互作用的影响及可能的机制，对肝脏脂肪变性、炎症和肝纤维化启动、持续的影响。从而阐明NASH发展中肝脏巨噬细胞/Kupffer细胞和HSC的交互作用在炎症-纤维化轴进展中的作用,明确PPARγ及相关信号途径在两者活化和交互影响中的作用，为NASH相关肝纤维化的预防和治疗提供新的思路和理论支持。

Initiation and sustained activation of axis of inflammation-fibrosis play an important role in the development of nonalcoholic steatohepatitis (NASH). Macrophage/Kupffer cell and hepatic stellate cell (HSC) play the critical role in the progression of inflammation and fibrosis. Nuclear receptor PPARγ exerts the potential anti-inflammatory and antifibrotic effect. Our recent studies have shown that manipulation of PPARγ activity could promote macrophage/Kupffer cell M1/M2 phenotype shifting and thereby prevent or promote high fat-induced inflammatory response. In the current study, we’ll investigate the cross-talk between macrophage/Kupffer cell and HSC in the development of NASH through in vivo animal models and in vitro cell experiments. Furthermore, the effect and the mechanism of manipulation of PPARγ activity on the cell’s cross-talk were explored. The association between PPARγ activity modulation and hepatic steatosis, inflammation and fibrosis was further investigated. Based on the findings of present study, we want to elucidate the role of cross-talk between macrophage/Kupffer cell and HSC in the development of NASH, and the role of PPARγ signal pathway on activation and cross-talk of these cells, and provide a new theoretical basis for NAFLD prevention and treatment.