Advertisement

Hepatocellular carcinoma and lifestyles

  • Uttara Saran
    Affiliations
    Hepatology, Department of Clinical Research, University of Berne, Berne, Switzerland

    University Clinic of Visceral Surgery and Medicine, Inselspital Berne, Berne, Switzerland
    Search for articles by this author
  • Bostjan Humar
    Affiliations
    Department of Visceral & Transplantation Surgery, University Hospital Zürich, Zürich, Switzerland
    Search for articles by this author
  • Philippe Kolly
    Affiliations
    Hepatology, Department of Clinical Research, University of Berne, Berne, Switzerland

    University Clinic of Visceral Surgery and Medicine, Inselspital Berne, Berne, Switzerland
    Search for articles by this author
  • Jean-François Dufour
    Correspondence
    Corresponding author. Address: University Clinic for Visceral Surgery and Medicine, Inselspital, Bern, Switzerland. Tel.: +41 31 632 26 95; fax: +41 31 632 97 65.
    Affiliations
    Hepatology, Department of Clinical Research, University of Berne, Berne, Switzerland

    University Clinic of Visceral Surgery and Medicine, Inselspital Berne, Berne, Switzerland
    Search for articles by this author
Published:September 01, 2015DOI:https://doi.org/10.1016/j.jhep.2015.08.028

      Summary

      The majority of hepatocellular carcinoma occurs over pre-existing chronic liver diseases that share cirrhosis as an endpoint. In the last decade, a strong association between lifestyle and hepatocellular carcinoma has become evident. Abundance of energy-rich food and sedentary lifestyles have caused metabolic conditions such as obesity and diabetes mellitus to become global epidemics. Obesity and diabetes mellitus are both tightly linked to non-alcoholic fatty liver disease and also increase hepatocellular carcinoma risk independent of cirrhosis. Emerging data suggest that physical activity not only counteracts obesity, diabetes mellitus and non-alcoholic fatty liver disease, but also reduces cancer risk. Physical activity exerts significant anticancer effects in the absence of metabolic disorders. Here, we present a systematic review on lifestyles and hepatocellular carcinoma.

      Abbreviations:

      ACC (acetyl coenzyme A carboxylase), BMI (body mass index), DM (diabetes mellitus), FAS (fatty acid synthase), β-HAD (β-hydroxyacyl-CoA dehydrogenase), HBV (hepatitis B virus), HCC (hepatocellular carcinoma), HCV (hepatitis C virus), IHF (intrahepatic fat), MDA (malondialdehyde), NAFLD (non-alcoholic fatty liver disease), NASH (non-alcoholic steatohepatitis), FFA (free fatty acids), OLETF (Otsuka Long-Evans Tokushima Fatty), NEFA (non-esterified fatty acids), PA (physical activity), SCD-1 (stearoyl-CoA desaturase-1), SREBPF (sterol regulatory element-binding transcription factor 1), TNF-α (tumor necrosis factor-α)

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Journal of Hepatology
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Moller H.
        • Mellemgaard A.
        • Lindvig K.
        • Olsen J.H.
        Obesity and cancer risk: a Danish record-linkage study.
        Eur J Cancer. 1994; 30A: 344-350
        • Wolk A.
        • Gridley G.
        • Svensson M.
        • Nyren O.
        • McLaughlin J.K.
        • Fraumeni J.F.
        • et al.
        A prospective study of obesity and cancer risk (Sweden).
        Cancer Causes Control. 2001; 12: 13-21
        • Calle E.E.
        • Rodriguez C.
        • Walker-Thurmond K.
        • Thun M.J.
        Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults.
        N Engl J Med. 2003; 348: 1625-1638
        • Samanic C.
        • Gridley G.
        • Chow W.H.
        • Lubin J.
        • Hoover R.N.
        • Fraumeni Jr., J.F.
        Obesity and cancer risk among white and black United States veterans.
        Cancer Causes Control. 2004; 15: 35-43
        • Batty G.D.
        • Shipley M.J.
        • Jarrett R.J.
        • Breeze E.
        • Marmot M.G.
        • Smith G.D.
        Obesity and overweight in relation to organ-specific cancer mortality in London (UK): findings from the original Whitehall study.
        Int J Obes (Lond). 2005; 29: 1267-1274
        • Samanic C.
        • Chow W.H.
        • Gridley G.
        • Jarvholm B.
        • Fraumeni Jr., J.F.
        Relation of body mass index to cancer risk in 362,552 Swedish men.
        Cancer Causes Control. 2006; 17: 901-909
        • Fedirko V.
        • Lukanova A.
        • Bamia C.
        • Trichopolou A.
        • Trepo E.
        • Nothlings U.
        • et al.
        Glycemic index, glycemic load, dietary carbohydrate, and dietary fiber intake and risk of liver and biliary tract cancers in Western Europeans.
        Ann Oncol. 2013; 24: 543-553
        • Berentzen T.L.
        • Gamborg M.
        • Holst C.
        • Sorensen T.I.
        • Baker J.L.
        Body mass index in childhood and adult risk of primary liver cancer.
        J Hepatol. 2014; 60: 325-330
        • Saunders D.
        • Seidel D.
        • Allison M.
        • Lyratzopoulos G.
        Systematic review: the association between obesity and hepatocellular carcinoma – Epidemiological evidence.
        Aliment Pharmacol Ther. 2010; 31: 1051-1063
        • El-Serag H.B.
        • Hampel H.
        • Javadi F.
        The association between diabetes and hepatocellular carcinoma: a systematic review of epidemiologic evidence.
        Clin Gastroenterol Hepatol. 2006; 4: 369-380
        • Davila J.A.
        • Morgan R.O.
        • Shaib Y.
        • McGlynn K.A.
        • El-Serag H.B.
        Diabetes increases the risk of hepatocellular carcinoma in the United States: a population based case control study.
        Gut. 2005; 54: 533-539
        • Wideroff L.
        • Gridley G.
        • Mellemkjaer L.
        • Chow W.H.
        • Linet M.
        • Keehn S.
        • et al.
        Cancer incidence in a population-based cohort of patients hospitalized with diabetes mellitus in Denmark.
        J Natl Cancer Inst. 1997; 89: 1360-1365
        • Staretz M.E.
        • Murphy S.E.
        • Patten C.J.
        • Nunes M.G.
        • Koehl W.
        • Amin S.
        • et al.
        Comparative metabolism of the tobacco-related carcinogens benzo[a]pyrene, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol, and N′-nitrosonornicotine in human hepatic microsomes.
        Drug Metab Dispos. 1997; 25: 154-162
        • Wang L.Y.
        • Chen C.J.
        • Zhang Y.J.
        • Tsai W.Y.
        • Lee P.H.
        • Feitelson M.A.
        • et al.
        4-Aminobiphenyl DNA damage in liver tissue of hepatocellular carcinoma patients and controls.
        Am J Epidemiol. 1998; 147: 315-323
        • Chen Z.M.
        • Liu B.Q.
        • Boreham J.
        • Wu Y.P.
        • Chen J.S.
        • Peto R.
        Smoking and liver cancer in China: case-control comparison of 36,000 liver cancer deaths vs. 17,000 cirrhosis deaths.
        Int J Cancer. 2003; 107: 106-112
        • Koh W.P.
        • Robien K.
        • Wang R.
        • Govindarajan S.
        • Yuan J.M.
        • Yu M.C.
        Smoking as an independent risk factor for hepatocellular carcinoma: the Singapore Chinese Health Study.
        Br J Cancer. 2011; 105: 1430-1435
        • Shih W.L.
        • Chang H.C.
        • Liaw Y.F.
        • Lin S.M.
        • Lee S.D.
        • Chen P.J.
        • et al.
        Influences of tobacco and alcohol use on hepatocellular carcinoma survival.
        Int J Cancer. 2012; 131: 2612-2621
        • Trichopoulos D.
        • Bamia C.
        • Lagiou P.
        • Fedirko V.
        • Trepo E.
        • Jenab M.
        • et al.
        Hepatocellular carcinoma risk factors and disease burden in a European cohort: a nested case-control study.
        J Natl Cancer Inst. 2011; 103: 1686-1695
        • Zhang X.F.
        • Wei T.
        • Liu X.M.
        • Liu C.
        • Lv Y.
        Impact of cigarette smoking on outcome of hepatocellular carcinoma after surgery in patients with hepatitis B.
        PLoS One. 2014; 9: e85077
        • Fattovich G.
        • Stroffolini T.
        • Zagni I.
        • Donato F.
        Hepatocellular carcinoma in cirrhosis: incidence and risk factors.
        Gastroenterology. 2004; 127: S35-S50
        • Donato F.
        • Tagger A.
        • Gelatti U.
        • Parrinello G.
        • Boffetta P.
        • Albertini A.
        • et al.
        Alcohol and hepatocellular carcinoma: the effect of lifetime intake and hepatitis virus infections in men and women.
        Am J Epidemiol. 2002; 155: 323-331
        • Yuan J.M.
        • Govindarajan S.
        • Arakawa K.
        • Yu M.C.
        Synergism of alcohol, diabetes, and viral hepatitis on the risk of hepatocellular carcinoma in blacks and whites in the U.S..
        Cancer. 2004; 101: 1009-1017
        • Gallus S.
        • Bertuzzi M.
        • Tavani A.
        • Bosetti C.
        • Negri E.
        • La Vecchia C.
        • et al.
        Does coffee protect against hepatocellular carcinoma?.
        Br J Cancer. 2002; 87: 956-959
        • Larsson S.C.
        • Wolk A.
        Coffee consumption and risk of liver cancer: a meta-analysis.
        Gastroenterology. 2007; 132: 1740-1745
        • Bravi F.
        • Bosetti C.
        • Tavani A.
        • Gallus S.
        • La Vecchia C.
        Coffee reduces risk for hepatocellular carcinoma: an updated meta-analysis.
        Clin Gastroenterol Hepatol. 2013; 11: e1411
        • Sang L.X.
        • Chang B.
        • Li X.H.
        • Jiang M.
        Consumption of coffee associated with reduced risk of liver cancer: a meta-analysis.
        BMC Gastroenterol. 2013; 13: 34
        • Lai G.Y.
        • Weinstein S.J.
        • Albanes D.
        • Taylor P.R.
        • McGlynn K.A.
        • Virtamo J.
        • et al.
        The association of coffee intake with liver cancer incidence and chronic liver disease mortality in male smokers.
        Br J Cancer. 2013; 109: 1344-1351
        • Bamia C.
        • Lagiou P.
        • Jenab M.
        • Trichopoulou A.
        • Fedirko V.
        • Aleksandrova K.
        • et al.
        Coffee, tea and decaffeinated coffee in relation to hepatocellular carcinoma in a European population: multicentre, prospective cohort study.
        Int J Cancer. 2015; 136: 1899-1908
        • Setiawan V.W.
        • Wilkens L.R.
        • Lu S.C.
        • Hernandez B.Y.
        • Le Marchand L.
        • Henderson B.E.
        Association of coffee intake with reduced incidence of liver cancer and death from chronic liver disease in the US multiethnic cohort.
        Gastroenterology. 2015; 148 (quiz e115): 118-125
        • Lagiou P.
        • Rossi M.
        • Tzonou A.
        • Georgila C.
        • Trichopoulos D.
        • La Vecchia C.
        Glycemic load in relation to hepatocellular carcinoma among patients with chronic hepatitis infection.
        Ann Oncol. 2009; 20: 1741-1745
        • Rossi M.
        • Lipworth L.
        • Maso L.D.
        • Talamini R.
        • Montella M.
        • Polesel J.
        • et al.
        Dietary glycemic load and hepatocellular carcinoma with or without chronic hepatitis infection.
        Ann Oncol. 2009; 20: 1736-1740
        • Mandair D.S.
        • Rossi R.E.
        • Pericleous M.
        • Whyand T.
        • Caplin M.
        The impact of diet and nutrition in the prevention and progression of hepatocellular carcinoma.
        Expert Rev Gastroenterol Hepatol. 2014; 8: 369-382
        • Yu M.W.
        • Hsieh H.H.
        • Pan W.H.
        • Yang C.S.
        • CHen C.J.
        Vegetable consumption, serum retinol level, and risk of hepatocellular carcinoma.
        Cancer Res. 1995; 55: 1301-1305
        • Talamini R.
        • Polesel J.
        • Montella M.
        • Dal Maso L.
        • Crispo A.
        • Tommasi L.G.
        • et al.
        Food groups and risk of hepatocellular carcinoma: a multicenter case-control study in Italy.
        Int J Cancer. 2006; 119: 2916-2921
        • Turati F.
        • Trichopoulos D.
        • Polesel J.
        • Bravi F.
        • Rossi M.
        • Talamini R.
        • et al.
        Mediterranean diet and hepatocellular carcinoma.
        J Hepatol. 2014; 60: 606-611
        • Petersen K.F.
        • Dufour S.
        • Feng J.
        • Befroy D.
        • Dziura J.
        • Dalla Man C.
        • et al.
        Increased prevalence of insulin resistance and nonalcoholic fatty liver disease in Asian-Indian men.
        Proc Natl Acad Sci U S A. 2006; 103: 18273-18277
        • Jones L.W.
        • Viglianti B.L.
        • Tashjian J.A.
        • Kothadia S.M.
        • Keir S.T.
        • Freedland S.J.
        • et al.
        Effect of aerobic exercise on tumor physiology in an animal model of human breast cancer.
        J Appl Physiol. 1985; 2010: 343-348
        • Keum N.
        • Ju W.
        • Lee D.H.
        • Ding E.L.
        • Hsieh C.C.
        • Goodman J.E.
        • et al.
        Leisure-time physical activity and endometrial cancer risk: dose-response meta-analysis of epidemiological studies.
        Int J Cancer. 2014; 135: 682-694
        • Aoi W.
        • Naito Y.
        • Hang L.P.
        • Uchiyama K.
        • Akagiri S.
        • Mizushima K.
        • et al.
        Regular exercise prevents high-sucrose diet-induced fatty liver via improvement of hepatic lipid metabolism.
        Biochem Biophys Res Commun. 2011; 413: 330-335
        • Wu Y.
        • Zhang D.
        • Kang S.
        Physical activity and risk of breast cancer: a meta-analysis of prospective studies.
        Breast Cancer Res Treat. 2013; 137: 869-882
        • Robsahm T.E.
        • Aagnes B.
        • Hjartaker A.
        • Langseth H.
        • Bray F.I.
        • Larsen I.K.
        Body mass index, physical activity, and colorectal cancer by anatomical subsites: a systematic review and meta-analysis of cohort studies.
        Eur J Cancer Prev. 2013; 22: 492-505
        • Sun J.Y.
        • Shi L.
        • Gao X.D.
        • Xu S.F.
        Physical activity and risk of lung cancer: a meta-analysis of prospective cohort studies.
        Asian Pac J Cancer Prev. 2012; 13: 3143-3147
        • Buffart L.M.
        • Singh A.S.
        • van Loon E.C.
        • Vermeulen H.I.
        • Brug J.
        • Chinapaw M.J.
        Physical activity and the risk of developing lung cancer among smokers: a meta-analysis.
        J Sci Med Sport. 2014; 17: 67-71
        • Pijpe A.
        • Manders P.
        • Brohet R.M.
        • Collee J.M.
        • Verhoef S.
        • Vasen H.F.
        • et al.
        Physical activity and the risk of breast cancer in BRCA1/2 mutation carriers.
        Breast Cancer Res Treat. 2010; 120: 235-244
        • Wen C.P.
        • Lin J.
        • Yang Y.C.
        • Tsai M.K.
        • Tsao C.K.
        • Etzel C.
        • et al.
        Hepatocellular carcinoma risk prediction model for the general population: the predictive power of transaminases.
        J Natl Cancer Inst. 2012; 104: 1599-1611
        • Behrens G.
        • Matthews C.E.
        • Moore S.C.
        • Freedman N.D.
        • McGlynn K.A.
        • Everhart J.E.
        • et al.
        The association between frequency of vigorous physical activity and hepatobiliary cancers in the NIH-AARP Diet and Health Study.
        Eur J Epidemiol. 2013; 28: 55-66
        • Arem H.
        • Moore S.C.
        • Park Y.
        • Ballard-Barbash R.
        • Hollenbeck A.
        • Leitzmann M.
        • et al.
        Physical activity and cancer-specific mortality in the NIH-AARP Diet and Health Study cohort.
        Int J Cancer. 2014; 135: 423-431
        • Kenfield S.A.
        • Stampfer M.J.
        • Giovannucci E.
        • Chan J.M.
        Physical activity and survival after prostate cancer diagnosis in the health professionals follow-up study.
        J Clin Oncol. 2011; 29: 726-732
        • Richman E.L.
        • Kenfield S.A.
        • Stampfer M.J.
        • Paciorek A.
        • Carroll P.R.
        • Chan J.M.
        Physical activity after diagnosis and risk of prostate cancer progression: data from the cancer of the prostate strategic urologic research endeavor.
        Cancer Res. 2011; 71: 3889-3895
        • Johnson N.A.
        • Sachinwalla T.
        • Walton D.W.
        • Smith K.
        • Armstrong A.
        • Thompson M.W.
        • et al.
        Aerobic exercise training reduces hepatic and visceral lipids in obese individuals without weight loss.
        Hepatology. 2009; 50: 1105-1112
        • van der Heijden G.J.
        • Wang Z.J.
        • Chu Z.D.
        • Sauer P.J.
        • Haymond M.W.
        • Rodriguez L.M.
        • et al.
        A 12-week aerobic exercise program reduces hepatic fat accumulation and insulin resistance in obese, Hispanic adolescents.
        Obesity (Silver Spring). 2010; 18: 384-390
        • Hallsworth K.
        • Fattakhova G.
        • Hollingsworth K.G.
        • Thoma C.
        • Moore S.
        • Taylor R.
        • et al.
        Resistance exercise reduces liver fat and its mediators in non-alcoholic fatty liver disease independent of weight loss.
        Gut. 2011; 60: 1278-1283
        • Zelber-Sagi S.
        • Nitzan-Kaluski D.
        • Goldsmith R.
        • Webb M.
        • Zvibel I.
        • Goldiner I.
        • et al.
        Role of leisure-time physical activity in nonalcoholic fatty liver disease: a population-based study.
        Hepatology. 2008; 48: 1791-1798
        • Johnson N.A.
        • Stannard S.R.
        • Thompson M.W.
        Muscle triglyceride and glycogen in endurance exercise: implications for performance.
        Sports Med. 2004; 34: 151-164
        • Hickman I.J.
        • Jonsson J.R.
        • Prins J.B.
        • Ash S.
        • Purdie D.M.
        • Clouston A.D.
        • et al.
        Modest weight loss and physical activity in overweight patients with chronic liver disease results in sustained improvements in alanine aminotransferase, fasting insulin, and quality of life.
        Gut. 2004; 53: 413-419
        • Perseghin G.
        • Lattuada G.
        • De Cobelli F.
        • Ragogna F.
        • Ntali G.
        • Esposito A.
        • et al.
        Habitual physical activity is associated with intrahepatic fat content in humans.
        Diabetes Care. 2007; 30: 683-688
        • Church T.S.
        • Kuk J.L.
        • Ross R.
        • Priest E.L.
        • Biltoft E.
        • Blair S.N.
        Association of cardiorespiratory fitness, body mass index, and waist circumference to nonalcoholic fatty liver disease.
        Gastroenterology. 2006; 130: 2023-2030
        • Nguyen-Duy T.B.
        • Nichaman M.Z.
        • Church T.S.
        • Blair S.N.
        • Ross R.
        Visceral fat and liver fat are independent predictors of metabolic risk factors in men.
        Am J Physiol Endocrinol Metab. 2003; 284: E1065-E1071
        • Stallknecht B.
        • Larsen J.J.
        • Mikines K.J.
        • Simonsen L.
        • Bulow J.
        • Galbo H.
        Effect of training on insulin sensitivity of glucose uptake and lipolysis in human adipose tissue.
        Am J Physiol Endocrinol Metab. 2000; 279: E376-E385
        • Polak J.
        • Moro C.
        • Klimcakova E.
        • Hejnova J.
        • Majercik M.
        • Viguerie N.
        • et al.
        Dynamic strength training improves insulin sensitivity and functional balance between adrenergic alpha 2A and beta pathways in subcutaneous adipose tissue of obese subjects.
        Diabetologia. 2005; 48: 2631-2640
        • Bae J.C.
        • Suh S.
        • Park S.E.
        • Rhee E.J.
        • Park C.Y.
        • Oh K.W.
        • et al.
        Regular exercise is associated with a reduction in the risk of NAFLD and decreased liver enzymes in individuals with NAFLD independent of obesity in Korean adults.
        PLoS One. 2012; 7: e46819
        • Kistler K.D.
        • Brunt E.M.
        • Clark J.M.
        • Diehl A.M.
        • Sallis J.F.
        • Schwimmer J.B.
        Physical activity recommendations, exercise intensity, and histological severity of nonalcoholic fatty liver disease.
        Am J Gastroenterol. 2011; 106 (quiz 469): 460-468
        • Krasnoff J.B.
        • Painter P.L.
        • Wallace J.P.
        • Bass N.M.
        • Merriman R.B.
        Health-related fitness and physical activity in patients with nonalcoholic fatty liver disease.
        Hepatology. 2008; 47: 1158-1166
        • Ioannou G.N.
        • Morrow O.B.
        • Connole M.L.
        • Lee S.P.
        Association between dietary nutrient composition and the incidence of cirrhosis or liver cancer in the United States population.
        Hepatology. 2009; 50: 175-184
        • Hannukainen J.C.
        • Nuutila P.
        • Borra R.
        • Kaprio J.
        • Kujala U.M.
        • Janatuinen T.
        • et al.
        Increased physical activity decreases hepatic free fatty acid uptake: a study in human monozygotic twins.
        J Physiol. 2007; 578: 347-358
        • Hannukainen J.C.
        • Borra R.
        • Linderborg K.
        • Kallio H.
        • Kiss J.
        • Lepomaki V.
        • et al.
        Liver and pancreatic fat content and metabolism in healthy monozygotic twins with discordant physical activity.
        J Hepatol. 2011; 54: 545-552
        • St George A.
        • Bauman A.
        • Johnston A.
        • Farrell G.
        • Chey T.
        • George J.
        Independent effects of physical activity in patients with nonalcoholic fatty liver disease.
        Hepatology. 2009; 50: 68-76
        • Hickman I.J.
        • Clouston A.D.
        • Macdonald G.A.
        • Purdie D.M.
        • Prins J.B.
        • Ash S.
        • et al.
        Effect of weight reduction on liver histology and biochemistry in patients with chronic hepatitis C.
        Gut. 2002; 51: 89-94
        • Sreenivasa Baba C.
        • Alexander G.
        • Kalyani B.
        • Pandey R.
        • Rastogi S.
        • Pandey A.
        • et al.
        Effect of exercise and dietary modification on serum aminotransferase levels in patients with nonalcoholic steatohepatitis.
        J Gastroenterol Hepatol. 2006; 21: 191-198
        • Fealy C.E.
        • Haus J.M.
        • Solomon T.P.
        • Pagadala M.
        • Flask C.A.
        • McCullough A.J.
        • et al.
        Short-term exercise reduces markers of hepatocyte apoptosis in nonalcoholic fatty liver disease.
        J Appl Physiol. 1985; 2012: 1-6
        • Kaibori M.
        • Ishizaki M.
        • Matsui K.
        • Nakatake R.
        • Yoshiuchi S.
        • Kimura Y.
        • et al.
        Perioperative exercise for chronic liver injury patients with hepatocellular carcinoma undergoing hepatectomy.
        Am J Surg. 2013; 206: 202-209
        • Gauthier M.S.
        • Couturier K.
        • Charbonneau A.
        • Lavoie J.M.
        Effects of introducing physical training in the course of a 16-week high-fat diet regimen on hepatic steatosis, adipose tissue fat accumulation, and plasma lipid profile.
        Int J Obes Relat Metab Disord. 2004; 28: 1064-1071
        • Schultz A.
        • Mendonca L.S.
        • Aguila M.B.
        • Mandarim-de-Lacerda C.A.
        Swimming training beneficial effects in a mice model of nonalcoholic fatty liver disease.
        Exp Toxicol Pathol. 2012; 64: 273-282
        • Aguiar e Silva M.A.
        • Vechetti-Junior I.J.
        • Nascimento A.F.
        • Furtado K.S.
        • Azevedo L.
        • Ribeiro D.A.
        • et al.
        Effects of swim training on liver carcinogenesis in male Wistar rats fed a low-fat or high-fat diet.
        Appl Physiol Nutr Metab. 2012; 37: 1101-1109
        • Rector R.S.
        • Thyfault J.P.
        • Morris R.T.
        • Laye M.J.
        • Borengasser S.J.
        • Booth F.W.
        • et al.
        Daily exercise increases hepatic fatty acid oxidation and prevents steatosis in Otsuka Long-Evans Tokushima Fatty rats.
        Am J Physiol Gastrointest Liver Physiol. 2008; 294: G619-G626
        • Gauthier M.S.
        • Couturier K.
        • Latour J.G.
        • Lavoie J.M.
        Concurrent exercise prevents high-fat-diet-induced macrovesicular hepatic steatosis.
        J Appl Physiol. 1985; 2003: 2127-2134
        • Rector R.S.
        • Uptergrove G.M.
        • Morris E.M.
        • Borengasser S.J.
        • Laughlin M.H.
        • Booth F.W.
        • et al.
        Daily exercise vs. caloric restriction for prevention of nonalcoholic fatty liver disease in the OLETF rat model.
        Am J Physiol Gastrointest Liver Physiol. 2011; 300: G874-G883
        • Linden M.A.
        • Meers G.M.
        • Ruebel M.L.
        • Jenkins N.T.
        • Booth F.W.
        • Laughlin M.H.
        • et al.
        Hepatic steatosis development with four weeks of physical inactivity in previously active, hyperphagic OLETF rats.
        Am J Physiol Regul Integr Comp Physiol. 2013; 304: R763-R771
        • Piguet A.C.
        • Saran U.
        • Simillion C.
        • Keller I.
        • Terracciano L.
        • Reeves H.L.
        • et al.
        Regular exercise decreases liver tumors development in hepatocyte-specific PTEN-deficient mice independently of steatosis.
        J Hepatol. 2015; 62: 1296-1303
        • He Y.
        • Zhang H.
        • Fu F.
        The effects of swimming exercise on high-fat-diet-induced steatohepatitis.
        J Sports Med Phys Fitness. 2008; 48: 259-265
        • Jiang W.
        • Zhu Z.
        • Thompson H.J.
        Dietary energy restriction modulates the activity of AMP-activated protein kinase, Akt, and mammalian target of rapamycin in mammary carcinomas, mammary gland, and liver.
        Cancer Res. 2008; 68: 5492-5499
        • Bakan I.
        • Laplante M.
        Connecting mTORC1 signaling to SREBP-1 activation.
        Curr Opin Lipidol. 2012; 23: 226-234
        • Takekoshi K.
        • Fukuhara M.
        • Quin Z.
        • Nissato S.
        • Isobe K.
        • Kawakami Y.
        • et al.
        Long-term exercise stimulates adenosine monophosphate-activated protein kinase activity and subunit expression in rat visceral adipose tissue and liver.
        Metabolism. 2006; 55: 1122-1128
        • Cintra D.E.
        • Ropelle E.R.
        • Vitto M.F.
        • Luciano T.F.
        • Souza D.R.
        • Engelmann J.
        • et al.
        Reversion of hepatic steatosis by exercise training in obese mice: the role of sterol regulatory element-binding protein-1c.
        Life Sci. 2012; 91: 395-401
        • Berglund E.D.
        • Kang L.
        • Lee-Young R.S.
        • Hasenour C.M.
        • Lustig D.G.
        • Lynes S.E.
        • et al.
        Glucagon and lipid interactions in the regulation of hepatic AMPK signaling and expression of PPARalpha and FGF21 transcripts in vivo.
        Am J Physiol Endocrinol Metab. 2010; 299: E607-E614
        • Haigis M.C.
        • Mostoslavsky R.
        • Haigis K.M.
        • Fahie K.
        • Christodoulou D.C.
        • Murphy A.J.
        • et al.
        SIRT4 inhibits glutamate dehydrogenase and opposes the effects of calorie restriction in pancreatic beta cells.
        Cell. 2006; 126: 941-954
        • Csibi A.
        • Fendt S.M.
        • Li C.
        • Poulogiannis G.
        • Choo A.Y.
        • Chapski D.J.
        • et al.
        The mTORC1 pathway stimulates glutamine metabolism and cell proliferation by repressing SIRT4.
        Cell. 2013; 153: 840-854
        • Kelly A.
        • Stanley C.A.
        Disorders of glutamate metabolism.
        Ment Retard Dev Disabil Res Rev. 2001; 7: 287-295
        • Dean D.
        • Daugaard J.R.
        • Young M.E.
        • Saha A.
        • Vavvas D.
        • Asp S.
        • et al.
        Exercise diminishes the activity of acetyl-CoA carboxylase in human muscle.
        Diabetes. 2000; 49: 1295-1300
        • Hutber C.A.
        • Rasmussen B.B.
        • Winder W.W.
        Endurance training attenuates the decrease in skeletal muscle malonyl-CoA with exercise.
        J Appl Physiol. 1985; 1997: 1917-1922
        • Laurent G.
        • German N.J.
        • Saha A.K.
        • de Boer V.C.
        • Davies M.
        • Koves T.R.
        • et al.
        SIRT4 coordinates the balance between lipid synthesis and catabolism by repressing malonyl CoA decarboxylase.
        Mol Cell. 2013; 50: 686-698
        • Wang J.X.
        • Yi Y.
        • Li Y.W.
        • Cai X.Y.
        • He H.W.
        • Ni X.C.
        • et al.
        Down-regulation of sirtuin 3 is associated with poor prognosis in hepatocellular carcinoma after resection.
        BMC Cancer. 2014; 14: 297
        • Zheng L.
        • Yang W.
        • Wu F.
        • Wang C.
        • Yu L.
        • Tang L.
        • et al.
        Prognostic significance of AMPK activation and therapeutic effects of metformin in hepatocellular carcinoma.
        Clin Cancer Res. 2013; 19: 5372-5380
        • Calvisi D.F.
        • Wang C.
        • Ho C.
        • Ladu S.
        • Lee S.A.
        • Mattu S.
        • et al.
        Increased lipogenesis, induced by AKT-mTORC1-RPS6 signaling, promotes development of human hepatocellular carcinoma.
        Gastroenterology. 2011; 140: 1071-1083
        • Wakai K.
        • Suzuki K.
        • Ito Y.
        • Watanabe Y.
        • Inaba Y.
        • Tajima K.
        • et al.
        Time spent walking or exercising and blood levels of insulin-like growth factor-I (IGF-I) and IGF-binding protein-3 (IGFBP-3): A large-scale cross-sectional study in the Japan Collaborative Cohort study.
        Asian Pac J Cancer Prev. 2009; 10: 23-27
        • Zhu Z.
        • Jiang W.
        • McGinley J.
        • Wolfe P.
        • Thompson H.J.
        Effects of dietary energy repletion and IGF-1 infusion on the inhibition of mammary carcinogenesis by dietary energy restriction.
        Mol Carcinog. 2005; 42: 170-176
        • Shan J.
        • Shen J.
        • Liu L.
        • Xia F.
        • Xu C.
        • Duan G.
        • et al.
        Nanog regulates self-renewal of cancer stem cells through the insulin-like growth factor pathway in human hepatocellular carcinoma.
        Hepatology. 2012; 56: 1004-1014
        • Hutnick N.A.
        • Williams N.I.
        • Kraemer W.J.
        • Orsega-Smith E.
        • Dixon R.H.
        • Bleznak A.D.
        • et al.
        Exercise and lymphocyte activation following chemotherapy for breast cancer.
        Med Sci Sports Exerc. 2005; 37: 1827-1835
        • Radom-Aizik S.
        • Zaldivar F.
        • Haddad F.
        • Cooper D.M.
        Impact of brief exercise on peripheral blood NK cell gene and microRNA expression in young adults.
        J Appl Physiol. 1985; 2013: 628-636
        • MacNeil B.
        • Hoffman-Goetz L.
        Effect of exercise on natural cytotoxicity and pulmonary tumor metastases in mice.
        Med Sci Sports Exerc. 1993; 25: 922-928
        • de Lima C.
        • Alves L.E.
        • Iagher F.
        • Machado A.F.
        • Bonatto S.J.
        • Kuczera D.
        • et al.
        Anaerobic exercise reduces tumor growth, cancer cachexia and increases macrophage and lymphocyte response in Walker 256 tumor-bearing rats.
        Eur J Appl Physiol. 2008; 104: 957-964
        • Park E.J.
        • Lee J.H.
        • Yu G.Y.
        • He G.
        • Ali S.R.
        • Holzer R.G.
        • et al.
        Dietary and genetic obesity promote liver inflammation and tumorigenesis by enhancing IL-6 and TNF expression.
        Cell. 2010; 140: 197-208
        • Tchernof A.
        • Nolan A.
        • Sites C.K.
        • Ades P.A.
        • Poehlman E.T.
        Weight loss reduces C-reactive protein levels in obese postmenopausal women.
        Circulation. 2002; 105: 564-569
        • Bastard J.P.
        • Jardel C.
        • Bruckert E.
        • Blondy P.
        • Capeau J.
        • Laville M.
        • et al.
        Elevated levels of interleukin 6 are reduced in serum and subcutaneous adipose tissue of obese women after weight loss.
        J Clin Endocrinol Metab. 2000; 85: 3338-3342
        • McTiernan A.
        Mechanisms linking physical activity with cancer.
        Nat Rev Cancer. 2008; 8: 205-211
        • Allgayer H.
        • Owen R.W.
        • Nair J.
        • Spiegelhalder B.
        • Streit J.
        • Reichel C.
        • et al.
        Short-term moderate exercise programs reduce oxidative DNA damage as determined by high-performance liquid chromatography-electrospray ionization-mass spectrometry in patients with colorectal carcinoma following primary treatment.
        Scand J Gastroenterol. 2008; 43: 971-978
        • Golbidi S.
        • Badran M.
        • Laher I.
        Antioxidant and anti-inflammatory effects of exercise in diabetic patients.
        Exp Diabetes Res. 2012; 2012: 941868
        • Esposito K.
        • Pontillo A.
        • Di Palo C.
        • Giugliano G.
        • Masella M.
        • Marfella R.
        • et al.
        Effect of weight loss and lifestyle changes on vascular inflammatory markers in obese women: a randomized trial.
        JAMA. 2003; 289: 1799-1804
        • Hulver M.W.
        • Houmard J.A.
        Plasma leptin and exercise: recent findings.
        Sports Med. 2003; 33: 473-482
        • Mueller O.
        • Villiger B.
        • O’Callaghan B.
        • Simon H.U.
        Immunological effects of competitive versus recreational sports in cross-country skiing.
        Int J Sports Med. 2001; 22: 52-59
        • Sloan R.P.
        • Shapiro P.A.
        • Demeersman R.E.
        • McKinley P.S.
        • Tracey K.J.
        • Slavov I.
        • et al.
        Aerobic exercise attenuates inducible TNF production in humans.
        J Appl Physiol. 1985; 2007: 1007-1011
        • Stewart L.K.
        • Flynn M.G.
        • Campbell W.W.
        • Craig B.A.
        • Robinson J.P.
        • Timmerman K.L.
        • et al.
        The influence of exercise training on inflammatory cytokines and C-reactive protein.
        Med Sci Sports Exerc. 2007; 39: 1714-1719
        • Allgayer H.
        • Nicolaus S.
        • Schreiber S.
        Decreased interleukin-1 receptor antagonist response following moderate exercise in patients with colorectal carcinoma after primary treatment.
        Cancer Detect Prev. 2004; 28: 208-213
        • Ji L.L.
        Exercise-induced modulation of antioxidant defense.
        Ann N Y Acad Sci. 2002; 959: 82-92
        • Dekker M.J.
        • Lee S.
        • Hudson R.
        • Kilpatrick K.
        • Graham T.E.
        • Ross R.
        • et al.
        An exercise intervention without weight loss decreases circulating interleukin-6 in lean and obese men with and without type 2 diabetes mellitus.
        Metabolism. 2007; 56: 332-338
        • Thompson D.
        • Markovitch D.
        • Betts J.A.
        • Mazzatti D.
        • Turner J.
        • Tyrrell R.M.
        Time course of changes in inflammatory markers during a 6-mo exercise intervention in sedentary middle-aged men: a randomized-controlled trial.
        J Appl Physiol. 1985; 2010: 769-779
        • Heemskerk V.H.
        • Daemen M.A.
        • Buurman W.A.
        Insulin-like growth factor-1 (IGF-1) and growth hormone (GH) in immunity and inflammation.
        Cytokine Growth Factor Rev. 1999; 10: 5-14
        • Friedenreich C.M.
        • Neilson H.K.
        • Woolcott C.G.
        • McTiernan A.
        • Wang Q.
        • Ballard-Barbash R.
        • et al.
        Changes in insulin resistance indicators, IGFs, and adipokines in a year-long trial of aerobic exercise in postmenopausal women.
        Endocr Relat Cancer. 2011; 18: 357-369
        • Vansaun M.N.
        Molecular pathways: adiponectin and leptin signaling in cancer.
        Clin Cancer Res. 2013; 19: 1926-1932
        • Roglans N.
        • Vila L.
        • Farre M.
        • Alegret M.
        • Sanchez R.M.
        • Vazquez-Carrera M.
        • et al.
        Impairment of hepatic Stat-3 activation and reduction of PPARalpha activity in fructose-fed rats.
        Hepatology. 2007; 45: 778-788
        • Vila L.
        • Roglans N.
        • Alegret M.
        • Sanchez R.M.
        • Vazquez-Carrera M.
        • Laguna J.C.
        Suppressor of cytokine signaling-3 (SOCS-3) and a deficit of serine/threonine (Ser/Thr) phosphoproteins involved in leptin transduction mediate the effect of fructose on rat liver lipid metabolism.
        Hepatology. 2008; 48: 1506-1516
        • Yoshimoto S.
        • Loo T.M.
        • Atarashi K.
        • Kanda H.
        • Sato S.
        • Oyadomari S.
        • et al.
        Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome.
        Nature. 2013; 499: 97-101