title: Ceramide, tumor necrosis factor and alcohol-induced liver disease.
abstract: BACKGROUND
  The pathogenesis of alcohol-induced liver disease (ALD) is incompletely known. One of the key processes mediating the progression of ALD involved the overproduction of tumor necrosis factor (TNF) and the susceptibility of hepatocytes to TNF-induced apoptosis by alcohol intake.
  
  
  METHODS
  Analyze the apoptotic signaling of TNF resulting in the targeting and subsequent recruitment of mitochondria to death pathways.
  
  
  RESULTS
  Studies in experimental animal models of the disease have provided evidence for the role of ceramide generated from acidic sphingomyelinase in the apoptotic signaling of TNF through recruitment of mitochondria. The mitochondrial pool of glutathione (mGSH) is a vital line of defense against oxidative stress by precluding the accumulation peroxides generated endogenously within mitochondria and as a cofactor of mitochondrial antioxidant enzymes. The depletion of mGSH by alcohol has been described to determine the susceptibility of hepatocytes to TNF-mediated cell death.
  
  
  CONCLUSIONS
  The level of mGSH determines the fate of hepatocytes to acidic sphingomyelinase activation by TNF and hence strategies aimed to replenish mGSH or to antagonize the generation of ceramide from acidic sphingomyelinase may be of therapeutic value for ALD.
authors.affiliation: Institut de Malalties Digestives, Hospital Clinic, and Departamento de Patologia Experimental, Instituto Investigaciones Biomedicas de Barcelona, Consejo Superior de Investigaciones Cientificas, Barcelona, Spain. checca229@yahoo.com
authors.forename: José C
authors.initials: JC
authors.lastname: Fernandez-Checa
authors.forename: Anna
authors.initials: A
authors.lastname: Colell
authors.forename: Montserrat
authors.initials: M
authors.lastname: Mari
authors.forename: Carmen
authors.initials: C
authors.lastname: García-Ruiz
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002518:Ceramides / Q000378:metabolism*; D002784:Cholesterol / Q000378:metabolism; D000431:Ethanol / Q000633:toxicity; D005978:Glutathione / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects; D006801:Humans; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008108:Liver Diseases, Alcoholic / Q000378:metabolism* / Q000473:pathology; D008930:Mitochondria, Liver / Q000378:metabolism; D048069:Tumor Necrosis Factors / Q000378:metabolism*
chemical_list: D002518:Ceramides; D048069:Tumor Necrosis Factors; D000431:Ethanol; D002784:Cholesterol; D005978:Glutathione