{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T14:24:23Z","timestamp":1791901463562,"version":"4.3.4"},"reference-count":56,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2023,7,24]],"date-time":"2023-07-24T00:00:00Z","timestamp":1690156800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"JST SPRING","award":["JPMJSP2144"],"award-info":[{"award-number":["JPMJSP2144"]}]},{"name":"JST SPRING","award":["23fk0210125h"],"award-info":[{"award-number":["23fk0210125h"]}]},{"name":"Shinshu Public Utility Foundation for Promotion of Medical Sciences 2022","award":["JPMJSP2144"],"award-info":[{"award-number":["JPMJSP2144"]}]},{"name":"Shinshu Public Utility Foundation for Promotion of Medical Sciences 2022","award":["23fk0210125h"],"award-info":[{"award-number":["23fk0210125h"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>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, &gt; 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.<\/jats:p>","DOI":"10.3390\/cancers15143744","type":"journal-article","created":{"date-parts":[[2023,7,25]],"date-time":"2023-07-25T01:27:32Z","timestamp":1690248452000},"page":"3744","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Establishment of Novel Mouse Model of Dietary NASH Rapidly Progressing into Liver Cirrhosis and Tumors"],"prefix":"10.3390","volume":"15","author":[{"given":"Qianqian","family":"Zheng","sequence":"first","affiliation":[{"name":"Department of Metabolic Regulation, Shinshu University School of Medicine, Matsumoto 390-8621, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masaya","family":"Kawaguchi","sequence":"additional","affiliation":[{"name":"Oriental Yeast Co., Ltd., Itabashi, Tokyo 174-8505, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hayato","family":"Mikami","sequence":"additional","affiliation":[{"name":"Oriental Yeast Co., Ltd., Itabashi, Tokyo 174-8505, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pan","family":"Diao","sequence":"additional","affiliation":[{"name":"Department of Metabolic Regulation, Shinshu University School of Medicine, Matsumoto 390-8621, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuguang","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Metabolic Regulation, Shinshu University School of Medicine, Matsumoto 390-8621, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhe","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Metabolic Regulation, Shinshu University School of Medicine, Matsumoto 390-8621, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takero","family":"Nakajima","sequence":"additional","affiliation":[{"name":"Department of Metabolic Regulation, Shinshu University School of Medicine, Matsumoto 390-8621, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0430-6819","authenticated-orcid":false,"given":"Takanobu","family":"Iwadare","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, Matsumoto 390-8621, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takefumi","family":"Kimura","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, Matsumoto 390-8621, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6773-2802","authenticated-orcid":false,"given":"Jun","family":"Nakayama","sequence":"additional","affiliation":[{"name":"Department of Molecular Pathology, Shinshu University School of Medicine, Matsumoto 390-8621, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3212-3836","authenticated-orcid":false,"given":"Naoki","family":"Tanaka","sequence":"additional","affiliation":[{"name":"Department of Global Medical Research Promotion, Shinshu University Graduate School of Medicine, Matsumoto 390-8621, Japan"},{"name":"International Relations Office, Shinshu University School of Medicine, Matsumoto 390-8621, Japan"},{"name":"Research Center for Social Systems, Shinshu University, Matsumoto 390-8621, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,7,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1016\/j.pharmthera.2017.05.011","article-title":"Targeting nuclear receptors for the treatment of fatty liver disease","volume":"179","author":"Tanaka","year":"2017","journal-title":"Pharmacol. 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