In vivo altered unfolded protein response and apoptosis in livers from lipopolysaccharide-challenged cirrhotic rats

Background/Aims Endoplasmic reticulum (ER)-related unfolded protein response (UPR) is mediated by PKR-like ER kinase (PERK), ATF6 and IRE1. PERK phosphorylates eukaryotic translation initiation factor-2α (eIF2α) to attenuate protein synthesis, including in NF-κB-dependent antiapoptotic proteins. We hypothesized that an altered UPR in the liver may sensitize cirrhotic livers to LPS-induced, TNFα-mediated apoptosis. Thus, we examined in vivo UPR and NF-κB activity in livers from cirrhotic and normal LPS-challenged rats. Methods Livers were harvested in rats that did or did not receive LPS. Results Under baseline conditions, no UPR was found in normal livers while PERK/eIF2α and ATF6 pathways were activated in cirrhotic livers. After LPS, in normal livers, the PERK/eIF2α pathway was transiently activated. ATF6 and IRE1 were activated. In cirrhotic livers, the PERK/eIF2α pathway remained elevated. ATF6 and IRE1 pathways were altered. LPS-induced, NF-κB-dependent antiapoptotic proteins increased in normal livers whereas their expression was blunted at the posttranscriptional level in cirrhotic livers. Conclusions Cirrhotic livers exhibit partial UPR activation in the basal state and full UPR, although altered, after LPS challenge. Sustained eIF2α phosphorylation, a hallmark of cirrhotic liver UPR, is associated with a lack of LPS-induced accumulation of NF-κB-dependent antiapoptotic proteins which may sensitize cirrhotic livers to LPS/TNFα-mediated apoptosis.