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

Background/Aims: Endoplasmic reticulurn (ER)-related unfolded protein response (UPR) is mediated by PKR-like ER kinase (PERK), ATF6 and IRE1. PERK phosphorylates eukaryotic translation initiation factor-2 alpha (eIF2 alpha) to attenuate protein synthesis, including in NF-kappa B-dependent antiapoptotic proteins. We hypothesized that an altered UPR in the liver may sensitize cirrhotic livers to LPS-induced, TNF alpha-mediated apoptosis. Thus, we examined in vivo UPR and NF-kappa B 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/eIF2 alpha and ATF6 pathways were activated in cirrhotic livers. After LPS, in normal livers, the PERK/eIF2 alpha pathway was transiently activated. ATF6 and IRE1 were activated. In cirrhotic livers, the PERK/eIF2a pathway remained elevated. ATF6 and IRE1 pathways were altered. LPS-induced, NF-kappa B-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 eIF2a phosphorylation, a hallmark of cirrhotic liver UPR, is associated with a lack of LPS-induced accumulation of NF-kappa B-dependent antiapoptotic proteins which may sensitize cirrhotic livers to LPS/TNF alpha-mediated apoptosis. (C) 2007 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.