PHLDA3在非酒精性脂肪肝病发生发展中的作用和机制研究

随着生活方式的改变，非酒精性脂肪肝病(NAFLD)已发展为全球第一大慢性肝病。肝脏脂质沉积可导致内质网应激，而PHLDA3已被证实在肝细胞内质网应激方面发挥重要调控作用。PHLDA3是主要定位在细胞膜上的一个信号转导分子，但PHLDA3在NAFLD中的功能尚不清楚。申请人前期发现，肝细胞中敲除PHLDA3抑制脂肪酸诱导的肝细胞脂质积累；而过表达PHLDA3促进脂肪酸诱导的肝细胞脂质积累。质谱和免疫共沉淀检测到PHLDA3与TGF-β激活激酶1（TAK1）结合，并促进p-p38和p-JNK的磷酸化活性。据此我们提出假说：PHLDA3可能通过TAK1调控内质网应激从而调控下游脂代谢相关基因表达，促进NAFLD的发生发展。本项目拟利用细胞模型和Phlda3肝细胞特异性敲除小鼠来明确PHLDA3在NAFLD中的作用和分子机制，并通过siPHLDA3注射NAFLD小鼠探究其成为潜在治疗靶点的可行性。

With the change of life style, non-alcoholic fatty liver disease (NAFLD) has gradually developed into the largest chronic liver disease in the world. Pleckstrin Homology Like Domain Family A Member 3 (PHLDA3) is an important signal transduction molecule mainly located on the cell membrane, however, the role of PHLDA3 in NAFLD remains unknown. Our preliminary findings showed that knockout of Phlda3 dramatically inhibited palmitic acid/ oleic acid–induced hepatic fat accumulation in hepatocytes. However, overexpression of Phlda3 dramatically increased palmitic acid/ oleic acid–induced hepatic fat accumulation in hepatocytes. PHLDA3 was detected to bind to TGF-β-activated kinase 1 (TAK1) by using co-immunoprecipitation assay and enhanced its downstream factors p-P38 and p-JNK activation. Based on these, we propose a hypothesis: PHLDA3 may exacerbate NAFLD through TAK1 by regulating its downstream gene expression. This project intends to use cell model and phlda3 knockout mice to clarify the role and specific molecular mechanism of phlda3 in NAFLD. This project will help to reveal the new mechanism of NAFLD and provide new functional molecules for the treatment of NAFLD.