FMO1-TMAO轴介导未折叠蛋白反应促进NAFLD的作用及机制研究

非酒精性脂肪性肝病是我国第一大慢性肝病，但其发病机制尚不完全清楚，且缺乏特效治疗药物。为了探索其发病机制，申请者前期研究应用生物信息学方法分析NAFLD患者的肝组织基因芯片找到了关键基因FMO1。通过预实验发现TMA主要导致FMO1升高，并且FMO1可以作为靶点调控TMAO的生成。再次应用生物信息学方法，我们发现TMAO在体内的主要作用是引起未折叠蛋白反应，其作用机制可能与TMAO抑制HSPA2、HSPA4和HSPA8从而导致未折叠蛋白聚集有关。进一步实验也证实TMAO可以激活肝细胞的未折叠蛋白反应。据此，我们推测TMA是通过FMO1-TMAO通路激活未折叠蛋白反应而促进NAFLD的发生与发展。本课题设计将从细胞水平和动物水平探讨FMO1-TMAO轴介导未折叠蛋白反应促进NAFLD的作用及机制，以期为NAFLD的预防和治疗提供新的思路和靶点。

Non-alcoholic fatty liver disease is the most prevalent chronic liver disease in China, but its pathogenesis is not fully understood. There is a lack of specific therapeutic drugs. In order to explore its pathogenesis, we analyzed a liver tissue gene chip of NAFLD patients by bioinformatics analysis. We found that FMO1 is a key gene in the pathogenesis of NAFLD. Through preliminary experiments, we found that TMA mainly leads to the increase of FMO1, and FMO1 can be used as a target to regulate the generation of TMAO. Using bioinformatics methods, we found that the main role of TMAO is to induce the unfolded protein response, and the mechanism may be related to the inhibitory effect of TMAO on HSPA2, HSPA4 and HSPA8, leading to the accumulation of unfolded proteins. Further experiments also confirmed that TMAO activated the unfolded protein response in liver cells. Therefore, it is reasonable to speculate that TMA, a metabolite of intestinal flora, activates the unfolded protein response through the FMO1-TMAO pathway, thus promoting the occurrence and development of NAFLD. The hypothesis will be verified from both cell and animal levels in this study, aiming to provide new ideas and targets for the prevention and treatment of NAFLD.