Quantitative analysis of the interaction of ethanol metabolism with gluconeogenesis and fatty acid oxidation in the perfused liver of fasted rats

Abstract

Ethanol is known to significantly affect gluconeogenesis and lipid metabolism in the liver, primarily by altering the redox ratio in both cytosol and mitochondria. The effect of ethanol was analyzed using a comprehensive, dynamic model of liver metabolism that takes into account sub-cellular compartmentation, detailed kinetics for the citric acid cycle, ethanol and acetaldehyde oxidation, and gluconeogenesis, and inter-compartmental transport of metabolites, including the malate-aspartate shuttle. The kinetic expression for alcohol dehydrogenase takes into account inhibition by ethanol and NADH. Simulations of perfusions of the rat liver were performed with various combinations of substrates (lactate, pyruvate, and fatty acids), with subsequent addition of ethanol to the perfusate. The model successfully predicts NADH/NAD+, in both cytosol and mitochondria, the expected directional flux of reducing equivalents between the two compartments during perfusion with different gluconeogenic precursors, and the effect of ethanol on glucose and ketone body production. This model can serve as a platform for in silico experiments investigating the effects of ethanol on the many dehydrogenases, and thus the major carbohydrate and lipid metabolic pathways in the liver, as well as potential effects of various drugs that may interact with ethanol.