PATHOGENESIS OF EXPERIMENTAL ALCOHOLIC LIVER DISEASE

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Objectives: To determine the mechanism of alcoholic liver disease so that dietary interventions and preventive medicine will make it possible to minimize this disease. Specific Aims: To produce alcoholic liver disease which closely resembles human ALD including fatty change, inflammation, necrosis, and fibrosis of the liver in rats fed defined diets and alcohol by continuous intragastric feeding. This dietary regimen is modified in a way that by changing only one dietary ingredient, i.e. fat, no ALD lesion develops when the rats are fed ethanol. The diet which produces ALD contains 25% of calories derived from corn oil. The diet which prevents ALD substitutes corn oil with tallow (25% of calories). Using these two diet regimens, the one that produces ALD and the one that does not, the rats will be analyzed for the presence of biochemical and morphologic abnormalities in order to identify which abnormalities are associated with ALD and which are not. The abnormalities associated with ALD will be considered suspect as involved in the mechanism of ALD and will be studied further. Preventive measures will be tested to determine which mechanisms are involved by therapeutic intervention. Mechanisms to be studied include: 1) energy metabolism of the liver using 31P MRS in vivo correlated with 02 tension in the liver during chronic alcohol feeding; 2) linoleic acid/arachidonic acid metabolism using GL chromatography and HPLC of metabolites and inhibitors of arachidonate metabolizing enzymes; 3) morphometric determination of Ito cell activation associated with liver fibrosis using the electron microscope; 4) succinic dehydrogenase histochemistry for alcohol-induced increased permeability in zone 3 liver cells; and 5) vitamin A metabolism in ALD.