The major objective of my alcoholism-related research is to characterize the liver associated pathology which results from chronic ethanol consumption. The major effort will be an investigation of those changes that occur in hepatic energy metabolism during the early (fatty liver) stage of ethanol-induced liver disease. Our previous studies have documented several ethanol-induced lesions in liver mitochondria. The intact hepatocyte will now be investigated to determine if the depression in mitochondrial function observed in vitro adversely affects the energy state of the liver cell. Experiments are designed to determine 1) ethanol-elicited alterations in hepatocyte energy metabolism and 2) changes in the in vivo functioning of the mitochondrion. Similar measurements will be implemented with pericentral and periportal hepatocytes to determine whether ethanol-elicited alterations in hepatic energy metabolism are greater in the pericentral than the periportal region of the lobule. These studies should provide information needed to evaluate the suggestion that ethanol-induced pericentral hypoxia is an etiological factor in development of alcohol-induced liver disease. The above investigation, which is designed to determine alterations in hepatic energy metabolism at the cellular and organelle levels, will be accompanied by a series of studies to investigate the molecular mechanism(s) by which ethanol elicits its effect(s) on the structure and function of the mitochondrion. The effect of chronic ethanol consumption on the structure of the mitochondrial ATP synthase will be determined since we have obtained evidence that both the catalytic properties and the subunit composition of this enzyme are altered in ethanol-fed rats. Studies will also be carried out to determine the effects of ethanol on expression of the mitochondrial genome. There is now evidence that suggests that those polypeptides encoded on the mitochondrial genome are present in lowered amounts in liver mitochondria from ethanol-fed animals. The studies described in this proposal are designed to confirm that this is, indeed, the case. Experiments are also outlined to determine if ethanol consumption depresses the biosynthesis of these polypeptides by altering transcription. These studies of the effects of ethanol on membrane-associated polypeptides will complement the extensive investigations currently in progress to establish the relationship between ethanol-elicited effects on membrane lipids and alterations in membrane function.
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