Endoplasmic Reticulum Stress Regulates Hepatocyte Growth Factor Expression In Hepatic Stellate Cells And Its Effect On Acute Liver Failure

Background:The aim of this study was to test whether suppression of endoplasmic reticulum(ER)stress maintains hepatocyte growth factor(HGF)expression by hepatic stellate cells(HSCs)and whether HGF plays an important role in alleviating acute liver failure(ALF)by suppressing ER stress.Methods:Cells of the rat hepatic stellate cell line HSC-T6 were treated with the ER stress agonists tunicamycin and thapsigargin,and ER stress inhibitors sodium 4-phenylbutyrate(4-PBA)and salubrinal.Recombinant lentivirus LV-eIf2a-shRNA-GFP was produced to block el 2? activated by ER stress.A rat ALF model was created by intraperitoneal injection of D-galactosamine and lipopolysaccharide,and 100 mg/kg 4-PBA was injected 6 h before injection as an inhibitor of ER stress.Levels of HGF,vascular endothelial growth factor(VEGF),glucose-regulated protein 78,eukaryotic translation initiation factor 2a(elf2?),phospho-eIF2a,activating transcription factor 4 and C/EBP(CCAAT/enhancer binding protein)homologous protein(CHOP)in vitro and in vivo were measured by quantitative RT-PCR,ELISA,immunohistochemical staining and western blotting.Results:Our results demonstrated that ER stress stimulated VEGF but inhibited HGF expression in HSC-T6 cells.Both the stimulation of VEGF and the inhibition of HGF could be partly prevented in the presence of 4-PBA or Salubrinal,and interfering elf2a mRNA proportionately down-regulated HGF expression.Inhibition of HGF expression was also observed in the ALF rat.Treatment with 4-PBA prevented the reduction of HGF level and increased the survival rate of ALF rats.Both 4-PBA and salubrinal can partly prevent HGF down-regulation through regulating elf2a levels that involves suppression of ER stress in HSCs and in the rat model.Conclusions:4-PBA improved the long-term survival rate of rats with ALF and alleviated liver damage by inhibiting ER stress through keeping HGF level normal.We conclude that suppression of ER stress alleviates ALF in the rat by maintaining HGF expression.