Metabolomic Profiling Distinction of Human Nonalcoholic Fatty Liver Disease Progression from a Common Rat Model

OBJECTIVE: Characteristic pathologic changes define the progression of steatosis to nonalcoholic steatohepatitis (NASH), and are correlated to metabolic pathways. A common rodent model of NASH is the methionine and choline deficient (MCD) diet. The objective of this study was to perform full metabolomic analyses on liver samples to determine which pathways are altered most pronouncedly in the human condition, and to compare these changes to rodent models of nonalcoholic fatty liver disease (NAFLD). METHODS: A principal components analysis for all 91 metabolites measured indicates that metabolome perturbation is greater and less varied for humans than for rodents. RESULTS: Metabolome changes in human and rat NAFLD were greatest for the amino acid and bile acid metabolite families (e.g. asparagine, citrulline, GABA, lysine); although, in many cases, the trends were reversed when compared between species (cholic acid, betaine). CONCLUSIONS: Overall, these results indicate that metabolites of specific pathways may be useful biomarkers for NASH progression, although these markers may not correspond to rodent NASH models. The MCD model may be useful when studying certain endpoints of NASH; however, the metabolomics results indicate important differences between humans and rodents in the biochemical pathogenesis of the disease.