A mathematical modeling of liver metabolism in perfused rat liver

Abstract

An in silico liver model developed by Chalhoub, E. (2013) was expanded to cover gluconeogenesis, lipid metabolism, alanine and ethanol oxidation metabolism in the perfused rat liver. A mathematical model was developed as a tool to predict fluxes and concentrations of various intermediate metabolites in response to diverse alterations in the perfusion of different exogenous substrate doses, especially: alanine, glutamine, lactate, pyruvate and a combination of these substrates with or without oleate and/or alcohol (ethanol). The model consists of key regulating reactions representing gluconeogenesis, glycolysis, fatty acid metabolism, alanine-glutamine metabolism, oxidative phosphorylation, and ketogenesis. Modified Michaelis-Menten kinetic equations accounting for ATP/ADP are used for regulating the various reactions in our model. Rate expressions were established using data from in vitro enzyme activity based on allosteric effectors, accounting for phosphorylation or dephosphorylation. Our simulated model predicts 8 scenarios of experimental data from 7 different published works independently validated the model. Results have shown that for alanine and glutamine we had an increase in net glucose production, which matched results reported by the literature papers. However, for the simulated net lactate production results did not hit the target as reported by literature papers. This might be due to the basal oleate or alanine concentrations. Thus, this calls for further tuning to get better results for lactate for our model to be more valid and to be used as a basis for estimating various clinical, and nutritional states. As a conclusion, this model is used to study important physiological states and test several hypotheses to reduce the amount of experiments.