肥胖症患者常具血清高浓度的肥胖基因产物瘦素，且更易发生肝纤维化。已表明瘦素与肝纤维化密切关联。肝星状细胞(HSC)的激活为肝纤维化发生的关键，此过程的基础是HSC中重要转录因子表达及活性的改变，研究已显示转录因子过氧化物酶体增殖物激活受体γ(PPARγ)为抑制HSC激活的关键因子。申请者发现在HSC中瘦素强烈抑制PPARγ表达。该项目旨在此研究基础上，利用体外HSC培养及ob/ob肥胖鼠(缺正常瘦素)的体内实验，以及质粒构建，启动子突变，凝胶阻滞实验，染色质免疫沉淀等技术系统阐明瘦素抑制PPARγ表达的复杂机制，包括：筛查出介导瘦素调控PPARγ表达的转录因子；瘦素影响相关转录因子所利用的信号途径；瘦素对PPARγ稳定性的影响；瘦素通过以上相关机制对HSC激活的作用。深入到瘦素对抑制HSC激活的关键因子的详细调控研究，无报道。该项目有益于阐明肥胖症患者易于发生肝纤维化的复杂分子机理。

Leptin is a product of the ob gene. Obesity is often accompanied by hyperleptinemia while obesity patients are more apt to develop liver fibrosis. Earlier studies have indicated that leptin is closely associated with liver fibrosis. Hepatic stellate cell (HSC) activation is the key step during the process of liver fibrosis and the process of HSC activation is based on the alterations in the expressions and activities of important transcription factors. Transcription factor peroxisome-proliferator activated receptor-gamma (PPARγ) was found to play a key role in inhibition of HSC activation. Our previous researches showed that leptin strongly inhibited PPARγ expression in HSCs. Based on this result, the present research program aimed to elucidate the complex mechanisms underlying the inhibitory effect of leptin on PPARγ expression in HSCs in vitro and in vivo (ob/ob mice) by using plasmid construction, promoter mutation, electrophoretic mobility shift assay, chromatin immunoprecipitation, and other techniques. The results from this research program will reveal the transcription factors mediating leptin's inhibition of PPARγexpression, the signaling pathways by which leptin affects those transcription factors, the effect of leptin on the stability of PPARγ protein, and the influence of leptin-induced inhibition of PPARγ through correlated mechanisms on HSC activation. The mechanisms underlying leptin inhibition of PPARγare still unknown. The data from the researches may have potential implications for clarifying the mechanisms of liver fibrogenesis associated with hyperleptinemia such as in obesity patients.