{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,6]],"date-time":"2026-05-06T11:06:43Z","timestamp":1778065603402,"version":"3.51.4"},"reference-count":25,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2021,2,14]],"date-time":"2021-02-14T00:00:00Z","timestamp":1613260800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cancer Science"],"published-print":{"date-parts":[[2021,4]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Nonalcoholic fatty liver disease (NAFLD) is an increasingly common condition, affecting up to 25% of the population worldwide. NAFLD has been linked to several conditions, including hepatic inflammation, fibrosis, and hepatocellular carcinoma (HCC), however the role of NAFLD in cholangitis and the development of cholangiocellular carcinoma (CCC) remains poorly understood. This study investigated whether a high\u2010fat diet (HFD) promotes cholangitis and the development of CCC in mice. We used liver\u2010specific E\u2010cadherin gene (<jats:italic>CDH1<\/jats:italic>) knockout mice, <jats:italic>CDH1<jats:sup>\u2206Liv<\/jats:sup><\/jats:italic>, which develop spontaneous inflammation in the portal areas along with periductal onion skin\u2010like fibrosis, similar to that of primary sclerosing cholangitis (PSC). An HFD or normal diet (ND) was fed to <jats:italic>CDH1<jats:sup>\u2206Liv<\/jats:sup><\/jats:italic> mice for 7\u00a0mo. In addition, <jats:italic>CDH1<jats:sup>\u2206Liv<\/jats:sup><\/jats:italic> mice were crossed with <jats:italic>LSL\u2010Kras<jats:sup>G12D<\/jats:sup><\/jats:italic> mice, fed an HFD, and assessed in terms of liver tumor development. The extent of cholangitis and number of bile ductules significantly increased in mice fed an HFD compared with ND\u2010administered <jats:italic>CDH1<jats:sup>\u2206Liv<\/jats:sup><\/jats:italic> mice. The numbers of Sox9 and CD44\u2010positive stem cell\u2010like cells were significantly increased in HFD mice. <jats:italic>LSL\u2010Kras<jats:sup>G12D<\/jats:sup><\/jats:italic> \/<jats:italic>CDH1<jats:sup>\u2206Liv<\/jats:sup><\/jats:italic> HFD mice exhibited increased aggressiveness along with the development of numerous HCC and CCC, whereas <jats:italic>LSL\u2010Kras<jats:sup>G12D<\/jats:sup><\/jats:italic>\/<jats:italic>CDH1<jats:sup>\u2206Liv<\/jats:sup><\/jats:italic> ND mice showed several macroscopic tumors with both HCC and CCC components. In conclusion, NAFLD exacerbates cholangitis and promotes the development of both HCC and CCC in mice.<\/jats:p>","DOI":"10.1111\/cas.14828","type":"journal-article","created":{"date-parts":[[2021,1,28]],"date-time":"2021-01-28T08:42:42Z","timestamp":1611823362000},"page":"1471-1480","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["NAFLD exacerbates cholangitis and promotes cholangiocellular carcinoma in mice"],"prefix":"10.1111","volume":"112","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0246-1594","authenticated-orcid":false,"given":"Shin","family":"Maeda","sequence":"first","affiliation":[{"name":"Department of Gastroenterology Yokohama City University Graduate School of Medicine Yokohama Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yohko","family":"Hikiba","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology Yokohama City University Graduate School of Medicine Yokohama Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hiroaki","family":"Fujiwara","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology Institute for Adult Diseases Asahi Life Foundation Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tsuneo","family":"Ikenoue","sequence":"additional","affiliation":[{"name":"Division of Clinical Genome Research Advanced Clinical Research Center The Institute of Medical Science The University of Tokyo Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Soichiro","family":"Sue","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology Yokohama City University Graduate School of Medicine Yokohama Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Makoto","family":"Sugimori","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology Yokohama City University Graduate School of Medicine 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