CHRONIC ALCOHOLISM AND LIVER ENERGY AND LIPID METABOLISM

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The long range objectives of our laboratory are to 1) investigate the effects of chronic ethanol consumption on hepatic energy metabolism and 2) determine if ethanol-elicited alterations in the energy state of hepatic tissue contribute to the development of the irreversible stages of alcohol-related liver damage. In this proposal studies are described to characterize ethanol-related changes in hepatic energy metabolism that occur at 1) the molecular level, 2) the level of the mitochondrion and 3) in hepatocytes from different regions of the liver lobule. Mitochondrial. Studies completed during the past granting period demonstrated that chronic ethanol consumption in rats resulted in significant alterations in the synthesis of proteins encoded by the mitochondrial genome. It was established that translation was depressed due to a decrease in the level of mitoribosomes. It is likely that the lesion is a depression in the concentration of mitoribosomal proteins since ribosomal RNA content is normal in mitochondria from ethanol-fed rats. In this proposal experiments are included to establish whether mitoribosomal protein levels are depressed. Other studies will determine which portion of the mechanism giving rise to the intact mitochondrial ribosome is affected by ethanol consumption. Molecular. The mitochondrial ATP synthase is one of the complexes of the oxidative phosphorylation system adversely affected by chronic ethanol consumption. One possibility for its depression are alterations in interactions with phospholipids, required for maintenance of its activity. Studies are designed to establish whether the mitochondrial phospholipid, cardiolipin, is an obligatory component of the fully active enzyme complex. This investigation will be followed by studies to determine if ethanol-elicited alterations in the acyl chain composition of cardiolipin explain some of the decreases in the activity of the ATP synthase complex. Hepatocyte. Observations made in the last granting period demonstrate that low oxygen tension in the liver lobule depresses hepatic energy metabolism more in ethanol consumers than in control populations. Experiments are designed to explore this phenomenon in more detail utilizing whole liver hepatocytes, and those from both the periportal and perivenous region of the liver lobule. Phosphorus NMR spectroscopy will be utilized heavily in these latter studies.