Metabolic flux determination in perfused livers by mass balance analysis: effect of fasting

Isolated perfused livers from fasted rats have been extensively studied to understand the underlying mechanisms of injury-induced acute and chronic changes in liver metabolism. In this study, we investigated the impact of fasting on perfused liver metabolism. The methodology we used combines a flux variability approach, sampling analysis and singular value decomposition (SVD) to analyze the data using the same metabolic reaction network for both fed and fasted livers. Considering both experimental observations and mathematical analysis, the results show that 24 h fasting results in a limited glucose production from glycogen and up-regulation of gluconeogenic pathway. Glutamate metabolism and fatty acid oxidation are also slightly up-regulated whereas aspartate metabolism is down-regulated after fasting. Moreover, SVD analysis elucidates that glycogen breakdown mainly affects the pentose phosphate pathway in fasted state whereas co-occurrence pattern associated with glycogen breakdown and glycolysis observed in flux samples of fed state is dominant. In conclusion, this analysis provides a detailed description of the metabolic changes in two different states, considering the entire steady state flux space and dominant flux patterns that capture the system variations within the flux space.