PPARα激活保护小鼠急性肝衰竭对CHOP的调节作用研究

Regulation of peroxisome proliferator-activated receptor alpha on CHOP in acute liver failure mice

目的探讨过氧化物酶体增殖物激活受体α(PPARα)激活对小鼠急性肝衰竭(acute liver failure,ALF)肝损伤保护过程中对内质网应激凋亡蛋白标志物CCAAT/增强子结合蛋白同源蛋白(CHOP)信号分子的影响。方法以C57BL/6小鼠为研究对象,腹腔注射D-氨基半乳糖(D-GalN)联合脂多糖(LPS)建立小鼠ALF模型。PPARα激活剂Wy-14643及siRNA分别对ALF小鼠模型进行干预,检测小鼠肝脏病理改变、血清转氨酶ALT、AST评价肝脏功能,免疫印迹、实时荧光定量PCR及免疫荧光方法检测CHOP的基因及蛋白表达水平。结果 D-GalN/LPS诱导ALF小鼠中,肝损伤程度及转氨酶水平随着时间延长逐渐加重,PPARα水平下降,CHOP水平上升。Wy-14643干预降低肝组织CHOP的表达水平,PPARαsiRNA干预增加肝组织CHOP的表达水平。结论 ALF肝损伤过程中,PPARα可通过调节CHOP参与内质网应激诱导的肝细胞凋亡,PPARα-CHOP信号通路可能是ALF致病分子机制之一。

Objective To investigate the effect of peroxisome proliferator activated receptor alpha(PPARα) on C/EBP homologous protein CHOP signaling in the D-galactosamine(D-GalN) combined with lipopolysaccharide(LPS)induced acute liver failure(ALF) mice.Methods In a murine model induced by D-GalN/LPS,PPARα activator Wy-14643 or siRNA was used to intervene in a mouse model of ALF,respectively.The pathological changes,serum transaminase ALT and AST were assessed.Western blotting,real-time fluorescent quantitative PCR and immunofluorescence were used to detect the expression of CHOP.Results In D-GalN/LPS-induced ALF,the degree of liver injury and transaminase levels were gradually increased with time,PPARα levels were decreased,and CHOP levels were increased.Wy-14643 intervention reduced the expression of CHOP in liver tissue,and PPARα inhibition increased the expression of CHOP in liver tissue.Conclusion PPARα can interfere with hepatocyte apoptosis induced by endoplasmic reticulum stress by regulating CHOP in ALF.PPARα-CHOP signaling pathway may be one of the molecular mechanism of ALF.