Establishment of Novel Mouse Model of Dietary NASH Rapidly Progressing into Liver Cirrhosis and Tumors

SIMPLE SUMMARY: Non-alcoholic steatohepatitis (NASH) may progress into liver cirrhosis and hepatocellular carcinoma (HCC). NASH has been recognized as a major cause of HCC, which is the third leading cause of cancer-related deaths worldwide. However, the development of drug therapy for NASH and ensuing liver cirrhosis and HCC has been limited due to the lack of reliable preclinical models of the NASH progression. Here, we developed a new diet-induced mouse model of NASH-liver cirrhosis-HCC sequence. Compared with the previous mouse model, this model demonstrated shorter occurrence of NASH, liver cirrhosis, and HCC and more similar pathological characteristics to humans. Considering the similarity to clinicopathological features of human NASH in addition to very high reproducibility, generality, and convenience, our mouse model is expected to be used for the development of novel compounds for the treatment of NASH patients. ABSTRACT: Non-alcoholic steatohepatitis (NASH), which is the most severe manifestation of non-alcoholic fatty liver disease (NAFLD), has been recognized as a major hepatocellular carcinoma (HCC) catalyst. However, the molecular mechanism of NASH-liver fibrosis-HCC sequence remains unclear and a specific and effective treatment for NASH has not yet been established. The progress in this field depends on the availability of reliable preclinical models which show the steady progression to NASH, liver cirrhosis, and HCC. However, most of the NASH mouse models that have been described to date develop NASH generally for more than 24 weeks and there is an uncertainty of HCC development. To overcome such shortcomings of experimental NASH studies, we established a novel NASH-HCC mouse model with very high reproducibility, generality, and convenience. We treated male C57BL/6J mice with a newly developed choline-deficient and methionine-restricted high-fat diet, named OYC-NASH2 diet, for 60 weeks. Treatment of OYC-NASH2 diet for 3 weeks revealed marked steatosis, lobular inflammation, and fibrosis, histologically diagnosed as NASH. Liver cirrhosis was observed in all mice with 48-week treatment. Liver nodules emerged at 12 weeks of the treatment, > 2 mm diameter liver tumors developed in all mice at 24 weeks of the treatment and HCC appeared after 36-week treatment. In conclusion, our rapidly progressive and highly reproducible NASH-liver cirrhosis-HCC model is helpful for preclinical development and research on the pathogenesis of human NAFLD-NASH-HCC. Our mouse model would be useful for the development of novel chemicals for NASH-HCC-targeted therapies.