Ceramide, tumor necrosis factor and alcohol-induced liver disease.
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.
Fernandez-Checa
José C
JC
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
Colell
Anna
A
Mari
Montserrat
M
García-Ruiz
Carmen
C
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*
D002518:Ceramides; D048069:Tumor Necrosis Factors; D000431:Ethanol; D002784:Cholesterol; D005978:Glutathione