OBJECTIVE: Characteristic pathological 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 this condition in humans, and to compare these changes to rodent models of nonalcoholic fatty liver disease (NAFLD). METHODS: A principal component analysis for all 91 metabolites measured indicated 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, gamma-aminobutyric acid, 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 end points of NASH; however, the metabolomics results indicate important differences between humans and rodents in the biochemical pathogenesis of the disease.

Biology Centre CAS Institute of Plant Molecular Biology Ceske Budejovice Czech Republic

Department of Pharmacology and Toxicology University of Arizona Tucson Arizona USA

Peking Union Medical College Hospital Chinese Academy of Medical Sciences Department of Clinical Laboratory Beijing China

Pharmaceutical Candidate Optimization Bristol Myers Squibb Co Princeton New Jersey USA

The Arizona Statistical Consulting Laboratory University of Arizona Tucson Arizona USA

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