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

INSERM U773, Centre de Recherche Bichat-Beaujon CRB3, Paris 75018, France.
Journal of Hepatology (Impact Factor: 11.34). 06/2007; 46(6):1075-88. DOI: 10.1016/j.jhep.2007.01.034
Source: PubMed


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.
Livers were harvested in rats that did or did not receive LPS.
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.
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.

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    • "In the context of Gramnegative infections, normal livers are protected against LPS-induced, TNF-αmediated apoptosis because of simultaneous induction of nuclear factor-κB (NF-κB)-dependent anti-apoptotic molecules [89]. In contrast, cirrhotic livers are abnormally susceptible to LPS-induced, TNF-α-mediated apoptosis because NF-κB-target anti-apoptotic molecules cannot be properly induced [89]. Therefore, in cirrhosis, infection-induced liver failure may be related not only to an excessive pro-inflammatory response but also to a decrease in the hepatic capacity of tolerance. "
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    • "In cirrhotic rat livers, only eIF2α was activated in the basal state. After LPS challenge, full UPR as indicated by activation of IRE1α, ATF-6, and eIF2α was detected [37]. However, LPS-induced accumulation of NF-κB-dependent antiapoptotic proteins was not observed, suggesting that the UPR sensitized the cirrhotic livers to LPS/TNFα-mediated apoptosis. "
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    01/2012; 2012(14):216450. DOI:10.1155/2012/216450
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    • "TNF, the major pro-inflammatory factor, has been shown to induce ER stress via increased ROS levels [8] [9] [10] [11]. Endotoxin (LPS) induces ER stress [12] by activating all three pathways specific for UPR via corresponding sensors, IRE1, PERK, and ATF6 [13] [14]. Since endotoxin evokes a systemic immune response, one can conclude that systemic immune response induces ER stress via pro-inflammatory factors in a reactive oxygen species ( "
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    ABSTRACT: Inflammatory response has recently been shown to induce endoplasmic reticulum (ER) stress and the unfolded protein response (UPR), which either recovers proper ER function or activates apoptosis. Here we show that endotoxin (lipopolysaccharide = LPS) can lead to functional ER failure tentatively via a mitochondrion-dependent pathway in livers of rats. Histological examination did not reveal significant damage to liver in form of necroses. Electron microscopy displayed transparent rings appearing around morphologically unchanged mitochondria, which were identified as dilated ER. The spliced mRNA variant of X-box protein-1 (XBP1) and also the mRNA of 78 kDa glucose-regulated protein (GRP78) were up-regulated, both typical markers of ER stress. However, GRP78 was down-regulated at the protein level. A pro-apoptotic shift in the bax/bcl-XL mRNA ratio was not accompanied by translocation of apoptosis inducing factor (AIF) to the nucleus, suggesting that the cells entered a pre-apoptotic state, but apoptosis was not executed. Monooxygenase activity of p450, representing the detoxification system in ER, was decreased after administration of endotoxin. Biochemical analysis of proteins important for ER function revealed the impairment of protein folding, transport, and detoxification suggesting functional ER failure. We suggest that functional ER failure may be a reason for organ dysfunction upon excessive inflammatory response mediated by endotoxin.
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