title: In vivo altered unfolded protein response and apoptosis in livers from lipopolysaccharide-challenged cirrhotic rats.
abstract: OBJECTIVE
  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-2alpha (eIF2alpha) to attenuate protein synthesis, including in NF-kappaB-dependent antiapoptotic proteins. We hypothesized that an altered UPR in the liver may sensitize cirrhotic livers to LPS-induced, TNFalpha-mediated apoptosis. Thus, we examined in vivo UPR and NF-kappaB 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/eIF2alpha and ATF6 pathways were activated in cirrhotic livers. After LPS, in normal livers, the PERK/eIF2alpha pathway was transiently activated. ATF6 and IRE1 were activated. In cirrhotic livers, the PERK/eIF2alpha pathway remained elevated. ATF6 and IRE1 pathways were altered. LPS-induced, NF-kappaB-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 eIF2alpha phosphorylation, a hallmark of cirrhotic liver UPR, is associated with a lack of LPS-induced accumulation of NF-kappaB-dependent antiapoptotic proteins which may sensitize cirrhotic livers to LPS/TNFalpha-mediated apoptosis.
authors.affiliation: INSERM U773, Centre de Recherche Bichat-Beaujon CRB3, Paris 75018, France.
authors.forename: Khalid A
authors.initials: KA
authors.lastname: Tazi
authors.forename: Ivan
authors.initials: I
authors.lastname: Bièche
authors.forename: Valérie
authors.initials: V
authors.lastname: Paradis
authors.forename: Cécile
authors.initials: C
authors.lastname: Guichard
authors.forename: Ingrid
authors.initials: I
authors.lastname: Laurendeau
authors.forename: Delphine
authors.initials: D
authors.lastname: Dargère
authors.forename: Agnès
authors.initials: A
authors.lastname: Legrand
authors.forename: Michèle
authors.initials: M
authors.lastname: Fay
authors.forename: Eric
authors.initials: E
authors.lastname: Pedruzzi
authors.forename: Marie-Anne
authors.initials: MA
authors.lastname: Robin
authors.forename: Dominique
authors.initials: D
authors.lastname: Cazals-Hatem
authors.forename: Zéra
authors.initials: Z
authors.lastname: Tellier
authors.forename: Dominique
authors.initials: D
authors.lastname: Bernuau
authors.forename: Gérard
authors.initials: G
authors.lastname: Feldmann
authors.forename: Michel
authors.initials: M
authors.lastname: Vidaud
authors.forename: Didier
authors.initials: D
authors.lastname: Lebrec
authors.forename: Eric
authors.initials: E
authors.lastname: Ogier-Denis
authors.forename: Richard
authors.initials: R
authors.lastname: Moreau
mesh_terms: D000818:Animals; D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D005355:Fibrosis / Q000473:pathology*; D008070:Lipopolysaccharides / Q000378:metabolism*; D008099:Liver / Q000378:metabolism / Q000473:pathology*; D008297:Male; D011489:Protein Denaturation; D017510:Protein Folding; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D015852:Eukaryotic Initiation Factor-2; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D053148:Caspase 3