Endoplasmic reticulum stress restrains hepatocyte growth factor expression in hepatic stellate cells and rat acute liver failure model.

The aim of this study was to test whether endoplasmic reticulum (ER) stress suppresses hepatocyte growth factor (HGF) expression in hepatic stellate cells (HSCs) and whether ER stress plays a role in alleviating d-Galactosamine and Lipopolysaccharide (D-GalN/LPS)-induced acute liver failure (ALF) by regulating HGF expression. Rat HSCs line HSC-T6 were treated with the ER stress inducers tunicamycin or thapsigargin, and ER stress inhibitors sodium 4-phenylbutyrate (4-PBA) or salubrinal, respectively. Recombinant lentivirus containing eukaryotic translation initiation factor 2α (eIf2α), named LV-eIf2α-shRNA-GFP was produced to block eIf2α activated by ER stress. A rat ALF model was created by intraperitoneal injection of D-GalN/LPS, and 100 mg/kg 4-PBA was injected 6 h before injection as an inhibitor of ER stress. Levels of HGF, c-Met, vascular endothelial growth factor (VEGF), GRP78, eIf2α, phospho-eIF2α, ATF4 and CHOP in vitro and in vivo were measured. 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 by 4-PBA or Salubrinal. eIf2α expression was upregulated during ERS and interfering eIf2α expression proportionately down-regulated HGF expression. Inhibition of HGF and c-Met expression was also observed in the ALF rat. Treatment with 4-PBA prevented the reduction of HGF in ALF rats. ER stress regulates HGF expression in vitro and in vivo, which depends on eIf2α pathway. Reduction in liver damage of ALF by 4-PBA is associated with attenuation of ER stress and maintaining HGF production.