Oxidative stress, antioxidants, and alcoholic liver fibrogenesis.
In the intragastric ethanol infusion model using a high fat diet (25% calories as corn oil) and adult Wistar rats, focal centrilobular liver necrosis is evident after five weeks of feeding, and liver fibrogenesis is induced between the 9th and 16th weeks. At the 16th week, fibroproliferative activation of Ito cells, a perisinusoidal cell type believed to be a key player in liver fibrogenesis, can be demonstrated by increased DNA synthesis, enhanced gene expression of collagen, and transforming growth factor-beta 1 (TGF beta 1) by these cells. This stage of alcoholic liver fibrogenesis, but not the earlier stage of liver necrosis, is closely associated with enhanced hepatic lipid peroxidation (LP) as demonstrated by significant correlation between the degree of liver fibrosis and hepatic levels of LP aldehydic products such as malondialdehyde (MDA) and 4-hydroxynonenal (4HNE). The direct role of these aldehydes in alcoholic liver fibrogenesis is supported by in vitro demonstration of stimulation of Ito cell collagen gene expression by MDA and 4HNE as well as in vivo confirmation of the importance of the aldehydes in iron-catalyzed potentiation of alcoholic liver fibrogenesis. Induced cytochrome P4502E1 is considered as a primary site of enhanced oxidative stress, and compromised glutathione homeostasis is suggested to underlie, in part, the net increase in hepatic LP. These findings are in support of our working hypothesis that enhanced LP is a critical pathogenetic event for alcoholic liver fibrogenesis.
Tsukamoto
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Department of Medicine, Case Western Reserve University, MetroHealth Medical Center, Cleveland, OH 44109.
D000447:Aldehydes / Q000494:pharmacology; D000818:Animals; D003094:Collagen / Q000235:genetics; D019392:Cytochrome P-450 CYP2E1; D003577:Cytochrome P-450 Enzyme System / Q000502:physiology; D004032:Diet; D005355:Fibrosis; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007501:Iron / Q000494:pharmacology; D008054:Lipid Peroxides / Q000378:metabolism*; D008099:Liver / Q000201:enzymology; D008108:Liver Diseases, Alcoholic / Q000209:etiology* / Q000473:pathology*; D008315:Malondialdehyde / Q000494:pharmacology; D009336:Necrosis; D010089:Oxidoreductases, N-Demethylating / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar
D000447:Aldehydes; D008054:Lipid Peroxides; D008315:Malondialdehyde; D003094:Collagen; D003577:Cytochrome P-450 Enzyme System; D007501:Iron; D019392:Cytochrome P-450 CYP2E1; D010089:Oxidoreductases, N-Demethylating; C027576:4-hydroxy-2-nonenal