An improved mouse model that rapidly develops fibrosis in non-alcoholic steatohepatitis

Int J Exp Pathol. 2013 Apr;94(2):93-103. doi: 10.1111/iep.12008. Epub 2013 Jan 11.


Non-alcoholic steatohepatitis (NASH) is a progressive fibrotic disease, the pathogenesis of which has not been fully elucidated. One of the most common models used in NASH research is a nutritional model where NASH is induced by feeding a diet deficient in both methionine and choline. However, the dietary methionine-/choline-deficient model in mice can cause severe weight loss and liver atrophy, which are not characteristics of NASH seen in human patients. Exclusive, long-term feeding with a high-fat diet (HFD) produced fatty liver and obesity in mice, but the HFD for several months did not affect fibrosis. We aimed to establish a mouse model of NASH with fibrosis by optimizing the methionine content in the HFD. Male mice were fed a choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD) consisting of 60 kcal% fat and 0.1% methionine by weight. After 1-14 weeks of being fed CDAHFD, the mice were killed. C57BL/6J mice maintained or gained weight when fed CDAHFD, while A/J mice showed a steady decline in body weight (of up to 20% of initial weight). In both strains of mice, plasma levels of alanine aminotransferase increased from week 1, when hepatic steatosis was also observed. By week 6, C57BL/6J mice had developed enlarged fatty liver with fibrosis as assessed by Masson's trichrome staining and by hydroxyproline assay. Therefore, this improved CDAHFD model may be a mouse model of rapidly progressive liver fibrosis and be potentially useful for better understanding human NASH disease and in the development of efficient therapies for this condition.

Keywords: fibrosis; high-fat diet; methionine-restricted diet; mouse model; non-alcoholic steatohepatitis.

MeSH terms

  • Alanine Transaminase / blood
  • Animals
  • Aspartate Aminotransferases / blood
  • Biomarkers / blood
  • Choline Deficiency
  • Diet, Fat-Restricted
  • Diet, High-Fat / adverse effects
  • Disease Models, Animal*
  • Fatty Liver / metabolism
  • Fatty Liver / pathology*
  • Humans
  • Liver / metabolism
  • Liver / pathology
  • Liver Cirrhosis / metabolism
  • Liver Cirrhosis / pathology*
  • Male
  • Methionine / deficiency
  • Mice
  • Mice, Inbred A
  • Mice, Inbred C57BL*
  • Non-alcoholic Fatty Liver Disease
  • Obesity
  • Specific Pathogen-Free Organisms
  • Time Factors


  • Biomarkers
  • Methionine
  • Aspartate Aminotransferases
  • Alanine Transaminase