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

Abstract

Summary 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. C 57 BL /6 J 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, C 57 BL /6 J mice had developed enlarged fatty liver with fibrosis as assessed by M asson'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.

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