The long-range goals of this project are to determine mechanisms of hepatotoxicity due to ethanol and ultimately to develop methods to prevent liver damage due to ethanol in human alcoholics. Because liver damage in alcoholics originates in pericentral regions of the liver lobule, we will acquire fundamental information on factors regulating metabolic compartmentation of key hepatic biochemical processes in pericentral regions of the liver lobule. For example, rates of metabolism of acyl CoA compounds and Alpha-glycerophosphate formation influence rates of triglyceride synthesis and induction of fatty liver due to ethanol; therefore, information on factors regulating the lobular distribution of glycolysis and ketogenesis will be useful in understanding pathologic events. By coupling specific microprobe detector systems developed in this laboratory to specific metabolic processes, we discovered that oxygen uptake, glycolysis and fatty acid oxidation occur at very different rates in pericentral and periportal regions of the liver lobule. Therefore, experiments will focus on the important question of whether enzyme, substrate or cofactor supply are major rate determinants for these metabolic processes in different regions of the lobule of the perfused liver. We will examine if rates of urea synthesis, gluconeogenesis, NADH redox state, triglyceride synthesis and rates of ethanol metabolism differ in periportal and pericentral regions of the liver lobule. Information on lobular metabolic compartmentation will be used to evaluate the role of hypoxia in mechanisms of alcohol-induced hepatotoxicity. Experiments will also evaluate the physiological role of H2O2 derived from peroxisomal fatty acid oxidation for catalase-H2O2 complex-dependent ethanol metabolism. In all of these studies the ADH-deficient deermouse will be used as a tool. To bridge the gap between in vitro and in vivo conditions where regulatory factors differ, oxygen uptake will be measured in periportal and pericentral regions of the living rat in situ. This is one of the only laboratories in the world dedicated to understanding mechanisms of metabolic compartmentation within the liver lobule using dynamic, non-invasive techniques. These studies will produce valuable data on important metabolic processes in periportal and pericentral regions of the liver lobule that will be used to elucidate mechanisms of ethanol-induced hepatotoxicity.
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