title: Regular exercise decreases liver tumors development in hepatocyte-specific PTEN-deficient mice independently of steatosis.
abstract: OBJECTIVE
  Unhealthy lifestyles predispose people to non-alcoholic steatohepatitis (NASH), which may further result in the development of hepatocellular carcinoma (HCC). Although NASH patients benefit from physical activity, it is unknown whether regular exercise reduces the risk of developing HCC. Therefore, we studied the effect of regular exercise on the development of HCC in male hepatocyte-specific PTEN-deficient mice (AlbCrePten(flox/flox)), which develop steatohepatitis and HCC spontaneously.
  
  
  METHODS
  Mice were fed a standardized 10% fat diet and were randomly divided into exercise or sedentary groups. The exercise group ran on a motorized treadmill for 60 min/day, 5 days/week during 32 weeks.
  
  
  RESULTS
  After 32 weeks of regular exercise, 71% of exercised mice developed nodules larger than 15 mm(3)vs. 100% of mice in the sedentary group. The mean number of tumors per liver was reduced by exercise, as well as the total tumoral volume per liver. Exercise did not affect steatosis and had no effect on the non-alcoholic fatty liver disease (NAFLD) Activity Score (NAS). Exercise decreased tumor cell proliferation. Mechanistically, exercise stimulated the phosphorylation of AMPK and its substrate raptor, which decreased the kinase activity of mTOR.
  
  
  CONCLUSIONS
  These data show a beneficial effect of regular exercise on the development of HCC in an experimental model of NASH and offer a rationale for encouraging predisposed patients to increase their physical activity for the prevention of HCC.
authors.affiliation: Hepatology, Department of Clinical Research, University of Berne, Berne, Switzerland.
authors.forename: Anne-Christine
authors.initials: AC
authors.lastname: Piguet
authors.affiliation: Hepatology, Department of Clinical Research, University of Berne, Berne, Switzerland.
authors.forename: Uttara
authors.initials: U
authors.lastname: Saran
authors.affiliation: Department of Clinical Research, University of Berne, Berne, Switzerland.
authors.forename: Cedric
authors.initials: C
authors.lastname: Simillion
authors.affiliation: Department of Clinical Research, University of Berne, Berne, Switzerland.
authors.forename: Irene
authors.initials: I
authors.lastname: Keller
authors.affiliation: Institute of Pathology, University Hospital of Basel, Basel, Switzerland.
authors.forename: Luigi
authors.initials: L
authors.lastname: Terracciano
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Newcastle-upon-Tyne, UK; The Liver Group, Newcastle University, Newcastle-upon-Tyne, UK.
authors.forename: Helen L
authors.initials: HL
authors.lastname: Reeves
authors.affiliation: Hepatology, Department of Clinical Research, University of Berne, Berne, Switzerland; University Clinic of Visceral Surgery and Medicine, Inselspital Berne, Berne, Switzerland. Electronic address: jf.dufour@insel.ch.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Dufour
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D001835:Body Weight; D005947:Glucose / Q000378:metabolism; D022781:Hepatocytes / Q000473:pathology / Q000502:physiology; D006801:Humans; D008099:Liver / Q000473:pathology; D008114:Liver Neoplasms, Experimental / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D065626:Non-alcoholic Fatty Liver Disease / Q000209:etiology / Q000473:pathology / Q000503:physiopathology; D051059:PTEN Phosphohydrolase / Q000172:deficiency* / Q000235:genetics; D010805:Physical Conditioning, Animal / Q000502:physiology*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse; D005947:Glucose
keywords: AMPK; Hepatocellular carcinoma; Non-alcoholic fatty liver disease; Non-alcoholic steatohepatitis; mTOR