In vivo altered unfolded protein response and apoptosis in livers from lipopolysaccharide-challenged cirrhotic rats.
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.
Tazi
Khalid A
KA
INSERM U773, Centre de Recherche Bichat-Beaujon CRB3, Paris 75018, France.
Bièche
Ivan
I
Paradis
Valérie
V
Guichard
Cécile
C
Laurendeau
Ingrid
I
Dargère
Delphine
D
Legrand
Agnès
A
Fay
Michèle
M
Pedruzzi
Eric
E
Robin
Marie-Anne
MA
Cazals-Hatem
Dominique
D
Tellier
Zéra
Z
Bernuau
Dominique
D
Feldmann
Gérard
G
Vidaud
Michel
M
Lebrec
Didier
D
Ogier-Denis
Eric
E
Moreau
Richard
R
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
D015852:Eukaryotic Initiation Factor-2; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D053148:Caspase 3