{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T03:21:32Z","timestamp":1790392892430,"version":"4.1.0"},"reference-count":55,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2020,5,29]],"date-time":"2020-05-29T00:00:00Z","timestamp":1590710400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"University Federico II of Naples and Compagnia di San Paolo","award":["STAR Program"],"award-info":[{"award-number":["STAR Program"]}]},{"DOI":"10.13039\/501100001711","name":"Schweizerischer Nationalfonds zur F\u00f6rderung der Wissenschaftlichen Forschung","doi-asserted-by":"publisher","award":["CRSII3_160717"],"award-info":[{"award-number":["CRSII3_160717"]}],"id":[{"id":"10.13039\/501100001711","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001711","name":"Schweizerischer Nationalfonds zur F\u00f6rderung der Wissenschaftlichen Forschung","doi-asserted-by":"publisher","award":["310030_185219"],"award-info":[{"award-number":["310030_185219"]}],"id":[{"id":"10.13039\/501100001711","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Non-alcoholic fatty liver disease (NAFLD) leads to steatohepatitis (NASH), fibrosis, and hepatocellular carcinoma. For sedentary patients, lifestyle interventions combining exercise and dietary changes are a cornerstone of treatment. However, the benefit of exercise alone when dietary changes have failed is uncertain. We query whether exercise alone arrests the progression of NASH and tumorigenesis in a choline-deficient, high-fat diet (CD-HFD) murine model. Male C57Bl\/6N mice received a control diet or CD-HFD for 12 weeks. CD-HFD mice were randomized further for 8 weeks of sedentariness (SED) or treadmill exercise (EXE). CD-HFD for 12 weeks produced NAFL. After 20 weeks, SED mice developed NASH and hepatic adenomas. Exercise attenuated the progression to NASH. EXE livers showed lower triglycerides and tumor necrosis factor-\u03b1 expression, less fibrosis, less ballooning, and a lower NAFLD activity score than did SED livers. Plasma transaminases and triglycerides were lower. Exercise activated AMP-activated protein kinase (AMPK) with inhibition of mTORC1 and decreased S6 phosphorylation, reducing hepatocellular adenoma. Exercise activated autophagy with increased LC3-II\/LC3-I and mitochondrial recruitment of phosphorylated PTEN-induced kinase. Therefore, exercise attenuates the transition from NAFL to NASH, improves biochemical and histological parameters of NAFLD, and impedes the progression of fibrosis and tumorigenesis associated with enhanced activation of AMPK signaling and favors liver autophagy. Our work supports the benefits of exercise independently of dietary changes.<\/jats:p>","DOI":"10.3390\/cancers12061407","type":"journal-article","created":{"date-parts":[[2020,6,2]],"date-time":"2020-06-02T09:19:27Z","timestamp":1591089567000},"page":"1407","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":50,"title":["Exercise Attenuates the Transition from Fatty Liver to Steatohepatitis and Reduces Tumor Formation in Mice"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0460-4122","authenticated-orcid":false,"given":"Maria","family":"Guarino","sequence":"first","affiliation":[{"name":"Hepatology, Department for BioMedical Research, University of Bern, 3008 Bern, Switzerland"},{"name":"Gastroenterology, Department of Clinical Medicine and Surgery, University of Naples \u201cFederico II\u201d, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pavitra","family":"Kumar","sequence":"additional","affiliation":[{"name":"Hepatology, Department for BioMedical Research, University of Bern, 3008 Bern, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Felser","sequence":"additional","affiliation":[{"name":"University Institute of Clinical Chemistry, Bern University Hospital, 3010 Bern, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luigi M.","family":"Terracciano","sequence":"additional","affiliation":[{"name":"Institute of Pathology, University Hospital Basel, 4056 Basel, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5748-1074","authenticated-orcid":false,"given":"Sergi","family":"Guix\u00e9-Muntet","sequence":"additional","affiliation":[{"name":"Hepatology, Department for BioMedical Research, University of Bern, 3008 Bern, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bostjan","family":"Humar","sequence":"additional","affiliation":[{"name":"Laboratory of the Swiss Hepato-Pancreato-Biliary (HPB) and Transplantation Center, Department of Surgery, University Hospital Z\u00fcrich, 8091 Z\u00fcrich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7199-4135","authenticated-orcid":false,"given":"Michelangelo","family":"Foti","sequence":"additional","affiliation":[{"name":"Department of Cell Physiology and Metabolism, University of Geneva, 1206 Geneva, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3650-6153","authenticated-orcid":false,"given":"Jean-Marc","family":"Nuoffer","sequence":"additional","affiliation":[{"name":"University Institute of Clinical Chemistry, Bern University Hospital, 3010 Bern, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie V.","family":"St-Pierre","sequence":"additional","affiliation":[{"name":"Hepatology, Department for BioMedical Research, University of Bern, 3008 Bern, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8062-1346","authenticated-orcid":false,"given":"Jean-Fran\u00e7ois","family":"Dufour","sequence":"additional","affiliation":[{"name":"Hepatology, Department for BioMedical Research, University of Bern, 3008 Bern, Switzerland"},{"name":"University Clinic of Visceral Surgery and Medicine, Inselspital Bern, 3010 Bern, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,5,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1002\/hep.28431","article-title":"Global epidemiology of nonalcoholic fatty liver disease\u2014Meta-analytic assessment of prevalence, incidence, and outcomes","volume":"64","author":"Younossi","year":"2016","journal-title":"Hepatology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"896","DOI":"10.1016\/j.jhep.2018.05.036","article-title":"Modeling NAFLD disease burden in China, France, Germany, Italy, Japan, Spain, United Kingdom, and United States for the period 2016\u20132030","volume":"69","author":"Estes","year":"2018","journal-title":"J. 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