NAFLD的主要问题之一是现有临床药物尚不能很好逆转肝脏内的脂质堆积，本课题选择肝脏内甘油三酯代谢的调控为切入点，揭示NAFLD的重要发病机制。我们首次建立了肝实质细胞条件敲除A1的小鼠 ，Alb-cre：hnRNP A1flox/flox，明确A1参与肝细胞甘油三酯代谢以及NAFLD的发病。使用RIP-Chip鉴定脂质代谢障碍时A1的结合基因，基于A1结合基因的多样性，首次提出靶向A1实现多方面网络调控NAFLD的概念。构建系列A1的拟磷酸化和非磷酸化突变体，明确A1蛋白核-浆定位与磷酸化修饰对其结合基因功能的影响。并且确立肝细胞A1作为NAFLD的药物靶标，证实其配体化合物调控甘油三酯代谢的可行性。希望通过本课题的研究，阐明A1及其结合基因对NAFLD病理机制的重要贡献，确立A1作为治疗NAFLD的新靶标，并为相关的药物发现打下基础。

One challenge of NAFLD is that the clinical drugs can not obviously reverse the lipid accumulation in liver. This project focuses on the regulation of triglyceride metabolism in liver as the check point for disease therapy, and will demonstrate the mechanism of hnRNP A1 in pathogenesis of NAFLD. Based on the previous studies, we established hepatocyte conditional knockout mice, Alb-cre: hnRNP A1flox/flox, to verify the important role of hnRNP A1 in NAFLD. RIP-Chip was used to indentify the hnRNP A1-targeting specific genes in dyslipidemia. Furthermore, site mutants are used to study hnRNP A1’s phosphorylation and cellular location in triglyceride metabolism. HnRNP A1 is confirmed to be the drug target for NALFD, and we will setup the drug evaluation system targeting hnRNP A1 and detect the improvement in NAFLD of candidate compounds. By this project, we will evaluate the contribution of hnRNP A1 and its targeting genes in triglyceride metabolism of hepatocyte, which maybe the novel strategies of NAFLD treatment.