(316g) A Model of Compartmentation and Redox Effects in the Fasted Perfused Liver

The effects of various substrates on the rates of gluconeogenesis and redox-associated metabolic pathways were investigated by means of a computational model of cytosol-mitochondrial compartmentation in the perfused liver of a fasted rat. The model includes detailed kinetics for the citric acid cycle, including inhibition and activation factors, inter-compartmental transport of metabolites, and the specialized carbon shuttle, the malate-aspartate shuttle. The model correctly predicts the NADH/NAD+ and ATP/ADP ratios in the cytosol and the mitochondria and the related reaction fluxes. In addition, the direction and rate of inter-compartmental transport of reducing equivalents are correctly predicted for perfusion with different gluconeogenic precursors. Hence this model serves as a platform for predicting the rates of many of the dehydrogenases participating in carbohydrate and lipid metabolism of the liver. Kinetic expressions for alcohol dehydrogenase (ADH), taking into account substrate inhibition and NADH inhibition, and aldehyde dehydrogenase were incorporated into the compartmental model. The alterations caused by ethanol to the level of cytosol and mitochondrial NADH/NAD+ and the resulting disturbances in both gluconeogenic and fatty acid metabolism were investigated by simulating lactate-ethanol and pyruvate?ethanol perfusions.