肝脂肪变性和胰岛素抵抗是慢性HCV感染者最显著的病理学特征,但相关分子机制尚不清楚,近期报道与脂肪代谢的重要调节因子-固醇调节元件结合蛋白（SREBPs）异常表达密切相关。我们在前期工作中发现3a基因型HCV编码的非结构蛋白5A（HCV-3a NS5A）调节肝癌细胞SREBP-1c的转录，影响其脂肪代谢。本项目在此基础上，应用小鼠肝细胞特异性表达重组NS5A的动物模型，继以不同时间和剂量的高脂饮食结合STZ诱导，在动物、组织和分子水平研究NS5A/SREBP-1对肝细胞糖脂代谢基因表达的影响，初步阐明NS5A/SREBP-1对HCV感染后易继发糖尿病的影响、以及NS5A/SREBP-1对肝细胞糖脂代谢的影响，为HCV相关糖尿病研究提供新的理论依据，为临床提供新的治疗靶点。

Steatosis and insulin resistance are important clinical manifestations of hepatitis C virus (HCV) infection. However, the precise mechanism underlying this association is still unclear. Recent studies demonstrated that sterol regulatory element binding proteins (SREBPs) may be essential components leading to glucose and lipid metabolism disorder associated with HCV infection. Our previous study has demonstrated that HCV Genotype 3 nonstructure 5A protein (HCV-3a NS5A) activates sterol regulatory element binding protein-1c (SREBP-1c) in Huh-7 hepatocarcinoma cell line and provide a mechanism of steatosis caused by HCV. In this proposal, we will develop a mice model by injection of recombimant HCV-3a NS5A lentivirus particles via tail intravenous which specifically expresses HCV-3a NS5A in hepatocyte, then followed by combining high fat diet with STZ injection. We will use above mice model to study the effect of HCV-3a NS5A on glucose and lipid metablism disorder by regulating SREBP-1a and SREBP-1c. The success of this study will help to reveal the molecular mechanism of HCV associated steatosis and insulin resistance, and it has great significance to explore the prevention and cure strategy of hepatitis C-related diabetes.