Mass flux balance-based model and metabolic flux analysis for collagen synthesis in the fibrogenesis process of human liver

A mass flux balance-based stoichiometric model for human liver metabolism has been set up. The model considers 125 reaction fluxes, and there are 83 metabolites that are assumed to be in pseudo-steady state. Theoretical metabolic flux distributions in the fibrotic and healthy liver cells were determined by maximizing respectively the collagen and palmitate synthesis in the objective function for the solution of the model, The flux distribution maps of the analysis for the collagen synthesis showed that the glycolysis pathway was active down to fructose-6-phosphate and the gluconeogenesis pathway was active up to glyceraldehyde 3-phosphate synthesis. However, the flux distribution maps for the palmitate synthesis revealed that both the glycolysis pathway and the gluconeogenesis pathway were active towards 3-phospho glycerate. The TCA cycle operated from citrate towards oxalacetate, and the anaplerotic reactions that connect the TCA cycle to the gluconeogenesis pathway were active in both analyses. Metabolic flux analysis shows that the amino acid fluxes are indeed important in the collagen synthesis. The results of the comparative analyses for the occurrence of the collagen synthesis in the fibrotic liver cells reveal that among the non-essential amino acids three, namely glycine, proline and aspartic acid, and among the essential amino acids one, methionine, are respectively the potential metabolic bottlenecks and the limiting amino acid. The diversions in the pathways and certain metabolic reactions are also presented, and potential strategies for controlling the collagen synthesis and consequently the fibrosis are also discussed. (C) 2000 Harcourt Publishers Ltd.