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.
Highlights
Model of Non-alcoholic fatty liver disease (NAFLD) without liver fibrosis in C57BL/6J mice fed high-fat diet (HFD) C57BL/6J mice were fed with standard diet (SD), HFD or low-fat diet with kcal% fat (LFD) for 24 weeks (Figure 1a)
We observed a substantial increase in the body weight of mice fed the HFD relative to the LFD
The livers showed that feeding of the HFD for 24 weeks promoted hepatocellular steatosis but without evidence of fibrosis (Figure 2)
Summary
We aimed to establish a mouse model of NASH with fibrosis by optimizing the methionine content in the HFD
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