TY - JOUR
T1 - Regular exercise decreases liver tumors development in hepatocyte-specific PTEN-deficient mice independently of steatosis
AU - Piguet, Anne Christine
AU - Saran, Uttara
AU - Simillion, Cedric
AU - Keller, Irene
AU - Terracciano, Luigi
AU - Reeves, Helen L.
AU - Dufour, Jean François
N1 - Funding Information:
This study was supported by the “Fatty Liver Inhibition of Progression” (FLIP) project funded by the European Union Seventh Framework Programme (FP7/2007–2013) under grant agreement Health-F2-2009-241762, Oncosuisse (grant number KFS-3506-08-2014) and the Swiss Science Foundation (Sinergia, grant number 141798) and the Swiss Foundation against Liver Cancer.
Funding Information:
This study was supported by the “Fatty Liver Inhibition of Progression” ( FLIP ) project funded by the European Union Seventh Framework Programme ( FP7/2007–2013 ) under grant agreement Health-F2-2009-241762, Oncosuisse (grant number KFS 2541-02-2010 ) and the Swiss Science Foundation (Sinergia, grant number 141798 ).
Publisher Copyright:
© 2015 European Association for the Study of the Liver.
PY - 2015/6/1
Y1 - 2015/6/1
N2 - Background & Aims 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 (AlbCrePtenflox/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 mm3 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.
AB - Background & Aims 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 (AlbCrePtenflox/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 mm3 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.
KW - AMPK
KW - Hepatocellular carcinoma
KW - mTOR
KW - Non-alcoholic fatty liver disease
KW - Non-alcoholic steatohepatitis
UR - http://www.scopus.com/inward/record.url?scp=84929606030&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84929606030&partnerID=8YFLogxK
U2 - 10.1016/j.jhep.2015.01.017
DO - 10.1016/j.jhep.2015.01.017
M3 - Article
C2 - 25623824
AN - SCOPUS:84929606030
SN - 0168-8278
VL - 62
SP - 1296
EP - 1303
JO - Journal of Hepatology
JF - Journal of Hepatology
IS - 6
M1 - 5520
ER -