A high intake of polyunsaturated fat is an important factor in the development of experimental alcoholic liver disease, but its role in humans needs further study. The whole spectrum of alcoholic liver disease, including fatty liver, necrosis, inflammation, and fibrosis, is reproduced in rats fed polyunsaturated triglycerides in the form of fish oil with continuous intragastric administration of ethanol. Such an extent of injury does not occur when the animals are fed saturated fat with the ethanol. In addition, the injury can be reversed after ethanol discontinuation by feeding a saturated, but not an unsaturated, fat diet. A prominent mechanism for the hepatic injury is the greater induction of cytochrome P450 2E1, which, during metabolism of various substrates, results in increased formation of oxygen radicals and lipid peroxidation causing injury to cell membranes and stimulating fibrosis. At the same time, increased metabolism of arachidonic acid results in greater formation of proinflammatory eicosanoids. Another possible factor for liver injury is increased formation of acetaldehyde- protein adducts such as the demonstrated formation of an adduct-a 37-kd liver protein. In contrast to these effects, polyunsaturated fatty acid deficiency may also be important in the pathogenesis of alcoholic liver disease, and administration of polyunsaturated lecithin prevents development of fibrosis in alcohol-fed baboons, an effect that is now being tested in a trial with alcoholic patients. Finally, preliminary studies with cholesterol supplementation suggest that cholesterol decreases hepatic necrosis and inflammation but increases the propensity to fibrosis in rats fed ethanol with polyunsaturated fat.
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