脂质代谢紊乱是影响慢性肝病患者病情进展的重要因素之一。我们的研究显示：重症肝炎小鼠体内载脂蛋白A-V(Apo A-V)表达明显降低，且在脂质代谢紊乱和慢性炎症相互作用过程中起桥梁作用的TLR4信号通路出现明显异常。 本项目拟通过建立化学性和免疫性两种不同类型的重症肝炎小鼠模型，并结合临床血清标本，观察Apo A-V水平降低是否对重症肝炎的发生具有早期预警作用；构建Apo A-V表达质粒，分析增加肝内Apo A-V表达对重症肝炎小鼠的死亡率及肝组织病理改变的影响，以阐明Apo A-V在重症肝炎发生中的可能作用。进一步通过检测肝组织中TLR4信号通路及关键分子的表达，并利用化学激动剂特异活化TLR4信号传导通路，了解Apo A-V在降低重症肝炎发生中的作用是否与TLR4信号传导通路有关。 本项目实施将有助于寻找预警重症肝炎发生的新指标和治疗重症肝炎的新靶点，并为阐明重症肝炎发生机制提供新思路。

Lipid metabolic disorder is one of the important factors affecting the progress of chronic liver disease. Our previous research showed that the expression of apolipoprotein A-V (Apo A-V) was significantly reduced in mouse with severe hepatitis; and TLR4 signaling pathway, which played a bridge role in lipid metabolism disorders and chronic inflammation was also activated in severe hepatitis mouse model. In this project, we plan to establish two different mouse models with severe hepatitis, and collect serum samples of patients with different severity of liver disease, so as to observe whether there is an early predicting warning effect of Apo A-V reduction in predicting the occurrence of severe hepatitis. By constructing a plasmid coding for mouse Apo A-V protein, we observe whether increasing the intrahepatic expression of Apo A-V could alleviate the mortality and liver pathological changes of mouse with severe hepatitis, so as to clarify the possible role of Apo A-V in severe hepatitis occurrence. By detecting TLR4 signaling pathway and its key molecules expression in severe hepatitis, and activating TLR4 signaling pathway via chemical agonists targeting its key molecules, we would clarify whether the role of Apo A-V in reducing severe hepatitis is correlated to TLR4 signaling pathway. The implementation of this project will help us to identify new indicators of early warning of severe hepatitis occurrence and new targets for the treatment of severe hepatitis, and also provide new ideas to elucidate the mechanism of severe hepatitis.