Metabonomic analysis of liver tissue from BALB/c mice with D-galactosamine/lipopolysaccharide-induced acute hepatic failure

Abstract

Background: Compared with biofluids, target tissues and organs more directly reflect the pathophysiological state of a disease process. In this study, a D-galactosamine (GalN) / lipopolysaccharide (LPS)-induced mouse model was constructed to investigate metabonomics of liver tissue and directly characterize metabolic changes in acute liver failure (ALF).

Methods: After pretreatment of liver tissue, gas chromatography coupled to time-of-flight mass spectrometry (GC/TOFMS) was used to separate and identify the liver metabolites. Partial least squares--discriminant analysis models were constructed to separate the ALF and control groups and to find those compounds whose liver levels differed significantly between the two groups.

Results: Distinct clustering was observed between the ALF and control mice. Fifty-eight endogenous metabolites were identified. Compared with the control mice, many metabolites, including sugars, amino acids, fatty acids, and organic acids, underwent significant changes in the ALF group, some of which differed from changes observed in plasma. Significant reduction of some important intermediate metabolites indicates that production of ketone bodies, the tricarboxylic acid and urea cycles, gluconeogenesis, glycolysis and pentose phosphate pathways are inhibited after GalN/LPS administration.

Conclusions: GC/TOFMS can be a powerful technique to perform metabonomic studies of liver tissue. GalN/LPS treatment can severely disturb substance metabolism in the liver, with different effects on metabolites compared with those observed in the plasma.

Figure 1

Comparison of GC/TOFMS total ion current (TIC) chromatographs of liver tissue from mice in the control (A) and ALF (B) groups. Each peak represents a metabolite, and the figures above the peaks represent their retention times.

Figure 2

Scores plot for PLS-DA of GC/TOFMS data derived from liver tissue of control and ALF mice. The scores plot shows distinct clustering of the control and ALF groups. Triangle and diamond shapes represent control and ALF model groups, respectively.