HepatoDyn: A Dynamic Model of Hepatocyte Metabolism That Integrates 13C Isotopomer Data

The liver performs many essential metabolic functions, which can be studied using computational models of hepatocytes. Here we present HepatoDyn, a highly detailed dynamic model of hepatocyte metabolism. HepatoDyn includes a large metabolic network, highly detailed kinetic laws, and is capable of dynamically simulating the redox and energy metabolism of hepatocytes. Furthermore, the model was coupled to the module for isotopic label propagation of the software package IsoDyn, allowing HepatoDyn to integrate data derived from 13C based experiments. As an example of dynamical simulations applied to hepatocytes, we studied the effects of high fructose concentrations on hepatocyte metabolism by integrating data from experiments in which rat hepatocytes were incubated with 20 mM glucose supplemented with either 3 mM or 20 mM fructose. These experiments showed that glycogen accumulation was significantly lower in hepatocytes incubated with medium supplemented with 20 mM fructose than in hepatocytes incubated with medium supplemented with 3 mM fructose. Through the integration of extracellular fluxes and 13C enrichment measurements, HepatoDyn predicted that this phenomenon can be attributed to a depletion of cytosolic ATP and phosphate induced by high fructose concentrations in the medium.
Author Summary Despite the key role of hepatocytes in carbohydrate and lipid homeostasis, available dynamic models of hepatocyte metabolism tend to be limited to a single pathway and/or are based on assumptions of constant concentrations of key metabolites involved in redox and energy metabolism (ATP, NAD, NADPH etc.). Furthermore, most dynamic models are unable to integrate information from 13C based experiments. 13C based experiments allow us to infer the relative activity of alternative pathways and hence are highly useful for indicating flux distributions. To overcome these limitations, we developed HepatoDyn, a dynamic model of hepatic metabolism. HepatoDyn uses a large metabolic network including key pathways such as glycolysis, the Krebs cycle, the pentose phosphate pathway and fatty acid metabolism, and dynamically models the concentrations of metabolites involved in the redox and energy metabolism of hepatocytes. In addition, the model was coupled to the label propagation module of the package IsoDyn, allowing it to integrate data from 13C based experiments to assist in the parametrization process. These features make HepatoDyn a powerful tool for studying the dynamics of hepatocyte metabolism.