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Alcoholic liver disease (ALD) is one the most serious consequences of chronic alcohol abuse. Liver cirrhosis, the culmination of the illness, is one of the leading causes of death in Western countries. Mitochondria are a target of ethanol intoxication mainly due to the toxic effects of acetaldehyde, a byproduct of ethanol metabolism. Morphological and functional changes in mitochondria are one of the key hallmarks of chronic ethanol exposure in both chronic alcoholics and experimental models of alcoholism. The functional changes observed in mitochondria from ethanol-treated animals are translated in an overall decrease in ATP levels resulting from a lower rate of ATP synthesis as a consequence of impaired processing at the translational level of some components of oxidative phosphorylation encoded by mitochondrial DNA genome. Mitochondrial glutathione (GSH) plays a critical role in the maintenance of cell functions and viability and in mitochondrial physiology by metabolism of oxygen free radicals generated in the respiratory chain. GSH in mitochondria originates from cytosol by a transport system which translocates GSH into the matrix. This transport system is impaired in chronic ethanol-fed rats, which translates in a selective and significant depletion of the mitochondrial GSH content resulting in the development of an increased susceptibility to oxidant stress. Using the intragastric infusion model of experimental ALD in rats, the profound and selective mitochondrial GSH depletion precedes the onset of alcoholic liver disease, mitochondrial lipid peroxidation, and progression of liver damage.(ABSTRACT TRUNCATED AT 250 WORDS)

AbstractSteatohepatitis represents an advanced stage of fatty liver disease that encompasses alcoholic (ASH) and non‐alcoholic steatohepatitis (NASH). The progression from steatosis to steatohepatitis is poorly understood. One of the clues to this progression is the sensitization of hepatocytes to oxidative stress and cytokine‐induced cell death. Mitochondrial glutathione (mGSH), which plays a central role in the control of mitochondrial reactive oxygen species (ROS) generation, modulates the sensitivity to cell death pathways. Mitochondrial GSH depletion due to alcohol‐mediated alteration in mitochondrial membrane dynamics underlies the susceptibility of hepatocytes from alcohol‐fed models to tumor necrosis factor (TNF), and in nutritional and genetic models of hepatic steatosis, mGSH depletion occurs due to the enrichment of mitochondria in free cholesterol, resulting in decreased mitochondrial membrane fluidity. The signaling of TNF through its membrane receptor TNFR1 from complex I to complex II is similar in hepatocytes depleted or not depleted in mGSH, yet hepatocellular susceptibility to TNF occurs if mGSH is depleted. Thus, mGSH is a critical factor in the development of steatohepatitis through sensitization of hepatocytes to inflammatory cytokines, and understanding the homeostasis of cholesterol and its trafficking to mitochondria may be of relevance in the pathophysiology of ASH and NASH.

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.