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Título

Oxidative stress and hepatocellular injury

AutorFernández-Checa, José C.
Fecha de publicación10-dic-2010
CitaciónAlcoholic Liver Disease (2010)
ResumenThe pathogenesis of alcoholic liver disease (ALD) is still incompletely known, although alcohol consumption has been described to sensitize hepatocytes to cell death pathways by depleting mitochondrial GSH (mGSH). Like other liver diseases, TNF-induced hepatocellular death is thought to play a role in ALD, as best demonstrated in experimental models. Its implication, however, in patients with ALD has been questioned due to controversial findings using strategies to antagonize TNF binding to its receptors. Since TNF is essential in regulating immunity, proliferation and survival signals, a better understanding of the signalling process involved in TNF-mediated hepatocellular injury may be of benefit in ALD. In this regard, ceramide generation by acidic sphingomyelinase (ASMase) plays an essential role in TNF-induced hepatocellular death (necrosis/apoptosis) by a dual mechanism involving ganglioside GD3 recruitment to mitochondria and subsequent generation of reactive oxygen species (ROS) and downregulation of MAT1A expression resulting in lower S-adenosyl-L-methionine levels. Moreover, ASMase null mice fed alcohol were resistant to both alcohol induced steatosis and circulating TNF (LPS)-induced hepatocellular injury. In contrast, alcohol sensitization to cell-bound (conA)-induced liver injury was still observed in ASMase-/- mice. Studies in TNF receptor1 (TNFR1) knockout mice, TNF receptor2 (TNFR2) knockout mice and double TNFR1/R2 knockout mice fed alcohol indicated a critical role for both receptors in alcohol-induced steatosis and sensitization to circulating and cell-bound TNF-mediated liver injury. Thus, the identification of downstream players in the apoptotic/necrotic pathways elicited by TNF, such as ASMase, may be a useful target for ALD as this approach does not interfere with the essential roles of TNF in immunity, proliferation and survival
DescripciónComunicación presentada en la Monothematic Conference "Alcoholic Liver Disease" de la European Association for the Study of the Liver (EASL), celebrada del 10 al 12 de diciembre de 2010 en Atenas (Grecia)
URIhttp://hdl.handle.net/10261/111809
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