Modeling energy depletion in rat livers using Nash equilibrium metabolic pathway analysis

Abstract

The current gold standard of Static Cold Storage (SCS), which is static cold storage on ice (about + 4 °C) in a specialized media such as the University of Wisconsin solution (UW), limits storage to few hours for vascular and metabolically active tissues such as the liver and the heart. The liver is arguably the pinnacle of metabolism in human body and therefore metabolic pathway analysis immediately becomes very relevant. In this article, a Nash Equilibrium (NE) approach, which is a first principles approach, is used to model and simulate the static cold storage and warm ischemia of a proposed model of liver cells. Simulations of energy depletion in the liver in static cold storage measured by ATP content and energy charge are presented along with comparisons to experimental data. In addition, conversion of Nash Equilibrium iterations to time are described along with an uncertainty analysis for the parameters in the model. Results in this work show that the Nash Equilibrium approach provides a good match to experimental data for energy depletion and that the uncertainty in model parameters is very small with percent variances less than 0.1%.

Optimal Temperature Protocols for Liver Machine Perfusion Using a Monte Carlo Method

“…The model of liver metabolism used in this paper is given in Lucia et al (2022) and consists of three cellular compartment – the cytosol, inner membrane, and mitochondria, 27 metabolic pathways, 64 chemical reactions involving mostly charged species, 309 metabolites and cofactors, 205 mass (charge) balances, and 81 model parameters (i.e., Gibbs free energies and enthalpies of formation). Figure 2 in Lucia et al (2022) is a superstructure representation of liver metabolism that includes inter-pathway transport.…”

“…In a recent paper, Lucia et al (2022) have successfully used a liver metabolism model and a Nash Equilibrium approach to simulate both SCS and warm ischemia. Numerical simulation results were compared with experimental data and demonstrate that the NE approach provides ‘good’ matches to experimental data.…”

“…In this paper, we use the liver metabolism model developed by Lucia et al (2022) to simulate liver machine perfusion and couple this with Monte Carlo simulation to determine optimal temperature protocols.…”

Optimized Partial Freezing Protocol Enables 10-Day Storage of Rat Livers

“…Metabolic depression relies on slowing the depletion of energy stores [14], [15] by lowering temperature.…”