Current concepts in the pathogenesis of alcoholic liver injury.
Alcoholic liver disease (ALD) develops as a consequence of priming and sensitizing mechanisms rendered by cross-interactions of primary mechanistic factors and secondary risk factors. This concept, albeit not novel, is becoming widely accepted by the field, and more research is directed toward identifying and characterizing the interfaces of the cross-interactions to help understand individual predisposition to the disease. Another pivotal development is the beginning of cell type-specific research to elucidate specific contributions not only of hepatocytes, but also of hepatic macrophages, liver-associated lymphocytes, sinusoidal endothelial cells, and hepatic stellate cells to sensitizing and priming mechanisms. In particular, the critical role of hepatic macrophages has been highlighted and the priming mechanisms concerning this paracrine effect have been proposed. Glutathione depletion in hepatocyte mitochondria is considered the most important sensitizing mechanism. One of the contributing factors is decreased methionine metabolism. Remaining key questions include how altered methionine metabolism contribute to the pathogenesis of ALD; how cross-talk among nonparenchymal liver cells or between nonparenchymal cells and hepatocytes leads to ALD; how dysfunctional mitochondria determine the type of cell death in ALD; and what secondary factors are critical for the development of advanced ALD such as alcoholic hepatitis and cirrhosis.
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USC-UCLA Research Center for Alcoholic Liver and Pancreatic Diseases, USC Research Center for Liver Diseases, Department of Pathology, Keck School of Medicine of USC, Los Angeles, California 90033, USA. htsukamo@hsc.usc.edu
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D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism; D004730:Endothelium, Vascular / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000473:pathology*; D008108:Liver Diseases, Alcoholic / Q000209:etiology* / Q000235:genetics / Q000473:pathology / Q000628:therapy; D008264:Macrophages / Q000378:metabolism; D008715:Methionine / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism
D008715:Methionine; D019392:Cytochrome P-450 CYP2E1