title: An improved mouse model that rapidly develops fibrosis in non-alcoholic steatohepatitis.
abstract: 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.
authors.affiliation: Fuji-Gotemba Research Laboratories, Chugai Research Institute for Medical Science Inc, Gotemba, Shizuoka, Japan.
authors.forename: Masahiko
authors.initials: M
authors.lastname: Matsumoto
authors.forename: Natsuko
authors.initials: N
authors.lastname: Hada
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Sakamaki
authors.forename: Akiko
authors.initials: A
authors.lastname: Uno
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Shiga
authors.forename: Chiaki
authors.initials: C
authors.lastname: Tanaka
authors.forename: Tsuneo
authors.initials: T
authors.lastname: Ito
authors.forename: Asao
authors.initials: A
authors.lastname: Katsume
authors.forename: Masayuki
authors.initials: M
authors.lastname: Sudoh
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D015415:Biomarkers / Q000097:blood; D002796:Choline Deficiency; D018752:Diet, Fat-Restricted; D059305:Diet, High-Fat / Q000009:adverse effects; D004195:Disease Models, Animal; D005234:Fatty Liver / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008103:Liver Cirrhosis / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008715:Methionine / Q000172:deficiency; D051379:Mice; D008805:Mice, Inbred A; D008810:Mice, Inbred C57BL; D065626:Non-alcoholic Fatty Liver Disease; D009765:Obesity; D013047:Specific Pathogen-Free Organisms; D013997:Time Factors
chemical_list: D015415:Biomarkers; D008715:Methionine; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase
keywords: fibrosis; high-fat diet; methionine-restricted diet; mouse model; non-alcoholic steatohepatitis