Exercise Attenuates the Transition from Fatty Liver to Steatohepatitis and Reduces Tumor Formation in Mice
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 f...
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2020-05-01
|
| Series: | Cancers |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2072-6694/12/6/1407 |
| _version_ | 1797566665374826496 |
|---|---|
| author | Maria Guarino Pavitra Kumar Andrea Felser Luigi M. Terracciano Sergi Guixé-Muntet Bostjan Humar Michelangelo Foti Jean-Marc Nuoffer Marie V. St-Pierre Jean-François Dufour |
| author_facet | Maria Guarino Pavitra Kumar Andrea Felser Luigi M. Terracciano Sergi Guixé-Muntet Bostjan Humar Michelangelo Foti Jean-Marc Nuoffer Marie V. St-Pierre Jean-François Dufour |
| author_sort | Maria Guarino |
| collection | DOAJ |
| description | 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-α 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. |
| first_indexed | 2024-03-10T19:29:42Z |
| format | Article |
| id | doaj.art-6fc0f7d4dd61411cb33f285ec42ff87c |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T19:29:42Z |
| publishDate | 2020-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-6fc0f7d4dd61411cb33f285ec42ff87c2023-11-20T02:13:55ZengMDPI AGCancers2072-66942020-05-01126140710.3390/cancers12061407Exercise Attenuates the Transition from Fatty Liver to Steatohepatitis and Reduces Tumor Formation in MiceMaria Guarino0Pavitra Kumar1Andrea Felser2Luigi M. Terracciano3Sergi Guixé-Muntet4Bostjan Humar5Michelangelo Foti6Jean-Marc Nuoffer7Marie V. St-Pierre8Jean-François Dufour9Hepatology, Department for BioMedical Research, University of Bern, 3008 Bern, SwitzerlandHepatology, Department for BioMedical Research, University of Bern, 3008 Bern, SwitzerlandUniversity Institute of Clinical Chemistry, Bern University Hospital, 3010 Bern, SwitzerlandInstitute of Pathology, University Hospital Basel, 4056 Basel, SwitzerlandHepatology, Department for BioMedical Research, University of Bern, 3008 Bern, SwitzerlandLaboratory of the Swiss Hepato-Pancreato-Biliary (HPB) and Transplantation Center, Department of Surgery, University Hospital Zürich, 8091 Zürich, SwitzerlandDepartment of Cell Physiology and Metabolism, University of Geneva, 1206 Geneva, SwitzerlandUniversity Institute of Clinical Chemistry, Bern University Hospital, 3010 Bern, SwitzerlandHepatology, Department for BioMedical Research, University of Bern, 3008 Bern, SwitzerlandHepatology, Department for BioMedical Research, University of Bern, 3008 Bern, SwitzerlandNon-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-α 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.https://www.mdpi.com/2072-6694/12/6/1407exerciseER stressnon-alcoholic fatty liver disease (NAFLD)non-alcoholic steatohepatitis (NASH)hepatocellular carcinoma (HCC)liver fibrosis |
| spellingShingle | Maria Guarino Pavitra Kumar Andrea Felser Luigi M. Terracciano Sergi Guixé-Muntet Bostjan Humar Michelangelo Foti Jean-Marc Nuoffer Marie V. St-Pierre Jean-François Dufour Exercise Attenuates the Transition from Fatty Liver to Steatohepatitis and Reduces Tumor Formation in Mice Cancers exercise ER stress non-alcoholic fatty liver disease (NAFLD) non-alcoholic steatohepatitis (NASH) hepatocellular carcinoma (HCC) liver fibrosis |
| title | Exercise Attenuates the Transition from Fatty Liver to Steatohepatitis and Reduces Tumor Formation in Mice |
| title_full | Exercise Attenuates the Transition from Fatty Liver to Steatohepatitis and Reduces Tumor Formation in Mice |
| title_fullStr | Exercise Attenuates the Transition from Fatty Liver to Steatohepatitis and Reduces Tumor Formation in Mice |
| title_full_unstemmed | Exercise Attenuates the Transition from Fatty Liver to Steatohepatitis and Reduces Tumor Formation in Mice |
| title_short | Exercise Attenuates the Transition from Fatty Liver to Steatohepatitis and Reduces Tumor Formation in Mice |
| title_sort | exercise attenuates the transition from fatty liver to steatohepatitis and reduces tumor formation in mice |
| topic | exercise ER stress non-alcoholic fatty liver disease (NAFLD) non-alcoholic steatohepatitis (NASH) hepatocellular carcinoma (HCC) liver fibrosis |
| url | https://www.mdpi.com/2072-6694/12/6/1407 |
| work_keys_str_mv | AT mariaguarino exerciseattenuatesthetransitionfromfattylivertosteatohepatitisandreducestumorformationinmice AT pavitrakumar exerciseattenuatesthetransitionfromfattylivertosteatohepatitisandreducestumorformationinmice AT andreafelser exerciseattenuatesthetransitionfromfattylivertosteatohepatitisandreducestumorformationinmice AT luigimterracciano exerciseattenuatesthetransitionfromfattylivertosteatohepatitisandreducestumorformationinmice AT sergiguixemuntet exerciseattenuatesthetransitionfromfattylivertosteatohepatitisandreducestumorformationinmice AT bostjanhumar exerciseattenuatesthetransitionfromfattylivertosteatohepatitisandreducestumorformationinmice AT michelangelofoti exerciseattenuatesthetransitionfromfattylivertosteatohepatitisandreducestumorformationinmice AT jeanmarcnuoffer exerciseattenuatesthetransitionfromfattylivertosteatohepatitisandreducestumorformationinmice AT marievstpierre exerciseattenuatesthetransitionfromfattylivertosteatohepatitisandreducestumorformationinmice AT jeanfrancoisdufour exerciseattenuatesthetransitionfromfattylivertosteatohepatitisandreducestumorformationinmice |