蛋白磷酸酶4经RAC1/MLK3/JNK信号通路调节肝细胞脂性凋亡参与NASH进程的机制研究

Lipotoxity-induced lipoapotosis promotes simple steotosis to non-alcoholic steotohepatitis(NASH).The activation of MLK3/JNK signaling plays an important role in this process. Protein phosphatase 4 (PP4) can regulate the metabolism of glucose and lipid in the liver. However the role of PP4 in NASH is still unknown. In the liver of FFC-diet fed mice, up-regulation of PP4 promotes the activation of MLK3/JNK signaling and hepatic lipoapoptosis, which accerated NASH process. It was reported that RAC1 was an important regulator of MLK3/JNK signaling. Our previous study showed that PP4 interacted with RAC1 and regulated RAC1 activity by dephosphorylation.Here we hypothesis that PP4 participates in the regulation of hepatic lipoapoptosis by dephosphorylating RAC1, which promotes NASH. To test the hypothesis, lipoapoptosis cell and animal models will be used to study the role of PP4 in hepatic lipoapoptosis and NASH, and mechanism by which RAC1/MLK3/JNK signaling regulated by PP4 and the role of PP4 involved in the lipoapoptosis and NASH process. This study will provide the novel idea for the prevention and treatment of NASH.

脂毒性引发的肝细胞脂性凋亡是单纯性脂肪肝进展为NASH的始动因素。MLK3/JNK是脂性凋亡中重要调控通路。PP4是肝脏糖脂代谢中新的调控因子，但它在NASH中的作用未见报道。我们首次发现：在单纯性脂肪肝小鼠肝脏中上调PP4的表达，激活了MLK3/JNK通路，加剧肝细胞的脂性凋亡，促进了NASH的进程。研究显示RAC1是MLK3/JNK通路的正调因子。在前期研究中,我们鉴定出PP4是RAC1新相互作用蛋白，且PP4可能通过去磷酸化修饰调节其活性。因此我们提出假说：PP4可能通过调节RAC1活性激活MLK3/JNK通路，进而调节肝细胞脂性凋亡，促进NASH进程。为验证该假说，我们建立脂性凋亡细胞模型及小鼠NASH模型，明确PP4在NASH中的作用，阐明PP4通过RAC1/MLK3/JNK信号通路参与NASH的作用机制。本项目的研究将为揭示NASH的发生机制奠定基础，为NASH防治提供新思路。

脂毒性引发的肝细胞脂性凋亡是单纯性脂肪肝进展为NASH的始动因素。MLK3/JNK是脂性凋亡中重要调控通路。PP4是肝脏糖脂代谢中新的调控因子，但它在NASH中的作用未见报道。我们首次发现：在单纯性脂肪肝小鼠肝脏中上调PP4的表达，激活了MLK3/JNK通路，加剧肝细胞的脂性凋亡，促进了NASH的进程。研究显示RAC1是MLK3/JNK通路的正调因子。在前期研究中,我们鉴定出PP4是RAC1新相互作用蛋白，且PP4可能通过去磷酸化修饰调节其活性。因此我们提出假说：PP4可能通过调节RAC1活性激活MLK3/JNK通路，进而调节肝细胞脂性凋亡，促进NASH进程。为验证该假说，我们建立脂性凋亡细胞模型及小鼠NASH模型，明确PP4在NASH中的作用，阐明PP4通过RAC1/MLK3/JNK信号通路参与NASH的作用机制。本项目的研究将为揭示NASH的发生机制奠定基础，为NASH防治提供新思路。