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01-12-2018 | Review

Role of exercise in the mechanisms ameliorating hepatic steatosis in non-alcoholic fatty liver disease

Authors: J. A. Russell-Guzmán, L. Karachon, T. A. Gacitúa, A. Freundlich, C. E. Poblete-Aro, R. Rodrigo

Published in: Sport Sciences for Health | Issue 3/2018

Abstract

Hepatic steatosis is an abnormal lipid accumulation within hepatocytes, generally present in non-alcoholic fatty liver disease (NAFLD) patients, a starting-point pathology currently associated with other clinical manifestations such as metabolic syndrome, non-alcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and eventually hepatocellular carcinoma. Hepatic steatosis in NAFLD may be induced by mechanisms such as insulin resistance, increased fatty acid uptake, a higher de novo lipogenesis from glucose or acetate, lower fatty acids oxidation and a decrease in fatty acid mobilization from liver. Among different therapeutic strategies appropriate for these patients, exercise has shown to be effective in reversing hepatic steatosis. However, the specific mechanisms involved in this response remain unclear. Therefore, the aim of this review is (1) to describe the mechanisms whereby exercise reverts hepatic steatosis, and (2) review the clinical outcomes of different exercise modalities in NAFLD parameters. Therefore, this knowledge may provide the basis suggesting potential clinical benefits of exercise as an adjunct therapy for patients with NAFLD and associated metabolic diseases.

Constanzo L (2011) Fisiología, 4th edn, chap 8. Elsevier, Barcelona, España (ISBN: 978-84-8086-824-2)

Adams LA, Angulo P (2005) Recent concepts in non-alcoholic fatty liver disease. Diabet Med 22(9) 1129–1133CrossRef

Adams LA, Angulo P, Lindor KD (2005) Nonalcoholic fatty liver disease. CMAJ 172(7):899–905CrossRef

Rector RS, Thyfault JP, Laye MJ, Morris RT, Borengasser SJ, Uptergrove GM, Chakravarthy MV, Booth FW, Ibdah JA (2008) Cessation of daily exercise dramatically alters precursors of hepatic steatosis in Otsuka Long-Evans Tokushima Fatty (OLETF) rats. J Physiol 586(Pt 17):4241–4249CrossRef

Rector RS, Thyfault JP, Morris RT, Laye MJ, Borengasser SJ, Booth FW, Ibdah JA (2008) Daily exercise increases hepatic fatty acid oxidation and prevents steatosis in Otsuka Long-Evans Tokushima Fatty rats. Am J Physiol Gastrointest Liver Physiol 294(3) G619–G626CrossRef

Videla L, Rodrigo R, Orellana M, Fernandez V, Tapia G, Quiñones L, Varela N, Contreras J, Lazarte R, Csendes A, Rojas J, Maluenda F, Burdiles P, Diaz JC, Smok G, Thielemann L, Poniachik J (2004) Oxidative stress-related parameters in the liver of non-alcoholic fatty liver disease patients. Clin Sci 106(3):261–268CrossRef

Patrick-Melin AJ, Kalinski MI, Kelly KR, Haus JM, Solomon TPJ, Kirwan JP (1999) Nonalcoholic fatty liver disease: biochemical and therapeutic considerations. Ukraïnsʹkyĭ biokhimichnyĭ zhurnal 81(5):16–25

Tilg H, Kaser A (2005) Treatment strategies in nonalcoholic fatty liver disease. Nat Clin Pract Gastroenterol Hepatol 2(3):148–155CrossRef

Willebrords J, Pereira IVA, Maes M, Crespo Yanguas S, Colle I, Van Den Bossche B, Da Silva TC, de Oliveira CPMS., Andraus W, Alves VA, Cogliati B, Vinken M (2015) Strategies, models and biomarkers in experimental non-alcoholic fatty liver disease research. Prog Lipid Res 59:106–125CrossRef

10.

Bouneva I, Kirby DF (2004) Management of nonalcoholic fatty liver disease: weight control. Clin Liver Dis 8(3) 693–713CrossRef

11.

Katsanos CS (2004) Lipid-induced insulin resistance in the liver: role of exercise. Sports Med 34(14):955–965CrossRef

12.

Perlemuter G, Bigorgne A, Cassard-Doulcier A-M, Naveau S (2007) Nonalcoholic fatty liver disease: from pathogenesis to patient care. Nat Clin Pract Endocrinol Metab 3(6):458–469CrossRef

13.

DeFronzo RA, Tripathy D (2009) Skeletal muscle insulin resistance is the primary defect in type 2 diabetes. Diabetes Care 32(Suppl 2):S157–S163CrossRef

14.

Pettinelli P, del Pozo T, Araya J, Rodrigo R, Araya AV, Smok G, Csendes A, Gutierrez L, Rojas J, Korn O, Maluenda F, Diaz JC, Rencoret G, Braghetto I, Castillo J, Poniachik J, Videla LA (2009) Enhancement in liver SREBP-1c/PPAR-α ratio and steatosis in obese patients: correlations with insulin resistance and n-3 long-chain polyunsaturated fatty acid depletion. Biochim Biophys Acta Mol Basis Dis 1792(11):1080–1086CrossRef

15.

Sanders FWB, Griffin JL (2016) De novo lipogenesis in the liver in health and disease: more than just a shunting yard for glucose. Biol Rev 91(2):452–468CrossRef

16.

Kohjima M, Higuchi N, Kato M, Kotoh K, Yoshimoto T, Fujino T, Yada M, Yada R, Harada N, Enjoji M, Takayanagi R, Nakamuta M (2008) SREBP-1c, regulated by the insulin and AMPK signaling pathways, plays a role in nonalcoholic fatty liver disease. Int J Mol Med 21(4):507–511PubMed

17.

Ferré P, Foufelle F (2010) Hepatic steatosis: a role for de novo lipogenesis and the transcription factor SREBP-1c. Diabetes Obes Metab 12(Suppl 2):83–92 (Figure 1) CrossRef

18.

Browning JD, Horton JD (2004) Molecular mediators of hepatic steatosis and liver injury. J Clin Invest 114(2):147–152CrossRef

19.

Pettinelli P, Videla La (2011) Up-regulation of PPAR-gamma mRNA expression in the liver of obese patients: an additional reinforcing lipogenic mechanism to SREBP-1c induction. J Clin Endocrinol Metab 96(5):1424–1430CrossRef

20.

Kersten S, Desvergne B, Wahli W (2000) Roles of PPARs in health and disease. Nature 405(6785):421–424CrossRef

21.

Houstis N, Rosen ED, Lander ES (2006) Reactive oxygen species have a causal role in multiple forms of insulin resistance. Nature 440:944–949CrossRef

22.

Rains JL, Jain SK (2011) Oxidative stress, insulin signaling, and diabetes. Free Radic Biol Med 50(5) 567–575CrossRef

23.

Pessayre D (2007) Role of mitochondria in non-alcoholic fatty liver disease. J Gastroenterol Hepatol 22(Suppl 1):S20–S27CrossRef

24.

Flamment M, Kammoun HL, Hainault I, Ferré P, Foufelle F (2010) Endoplasmic reticulum stress: a new actor in the development of hepatic steatosis. Curr Opin Lipidol 21(3):239–246CrossRef

25.

Király MA, Campbell J, Park E, Bates HE, Yue JTY, Rao V, Matthews SG, Bikopoulos G, Rozakis-Adcock M, Giacca A, Vranic M, Riddell MC (2010) Exercise maintains euglycemia in association with decreased activation of c-Jun NH2-terminal kinase and serine phosphorylation of IRS-1 in the liver of ZDF rats. Am J Physiol Endocrinol Metab 298(3):E671–E682CrossRef

26.

Park HS, Kim MW, Shin ES (1995) Effect of weight control on hepatic abnormalities in obese patients with fatty liver. J Korean Med Sci 10(6):414–421CrossRef

27.

Ueno T, Sugawara H, Sujaku K, Hashimoto O, Tsuji R, Tamaki S, Torimura T, Inuzuka S, Sata M, Tanikawa K (1997) Therapeutic effects of restricted diet and exercise in obese patients with fatty liver. J Hepatol 27(1)103–107CrossRef

28.

Magkos F (2010) Exercise and fat accumulation in the human liver. Curr Opin Lipidol 21(6)507–517CrossRef

29.

Gauthier M-S, Couturier K, Latour J-G, Lavoie J-M (2003) Concurrent exercise prevents high-fat-diet-induced macrovesicular hepatic steatosis. J Appl Physiol 94(6):2127–2134CrossRef

30.

Camacho RC, Donahue EP, James FD, Berglund ED, Wasserman DH (2006) Energy state of the liver during short-term and exhaustive exercise in C57BL/6J mice. Am J Physiol Endocrinol Metab 290(3) E405–E408CrossRef

31.

Trefts E, Williams AS, Wasserman DH (2015) Exercise and the regulation of hepatic metabolism. Prog Mol Biol Transl Sci 135:203–225CrossRef

32.

Ruderman NB, Park H, Kaushik VK, Dean D, Constant S, Prentki M, Saha AK (2003) AMPK as a metabolic switch in rat muscle, liver and adipose tissue after exercise. Acta Physiol Scand 178(4):435–442CrossRef

33.

Li Y, Xu S, Mihaylova MM, Zheng B, Hou X, Jiang B, Park O, Luo Z, Lefai E, Shyy JY-J, Gao B, Wierzbicki M, Verbeuren TJ, Shaw RJ, Cohen RA, Zang M (2011) AMPK phosphorylates and inhibits SREBP activity to attenuate hepatic steatosis and atherosclerosis in diet-induced Insulin-resistant mice. Cell Metab 13(4):376–388CrossRef

34.

Cintra DE, Ropelle ER, Vitto MF, Luciano TF, Souza DR, Engelmann J, Marques SO, Lira FS, De Pinho Ra, Pauli JR, De Souza CT (2012) Reversion of hepatic steatosis by exercise training in obese mice: the role of sterol regulatory element-binding protein-1c. Life Sci 91(11–12) :395–401CrossRef

35.

Alex S, Boss A, Heerschap A, Kersten S (2015) Exercise training improves liver steatosis in mice. Nutr Metab (Lond) 12(1):29CrossRef

36.

Vitto MF, Luz G, Luciano TF, Marques SO, Souza DR, Pinho RA, Lira FS, Cintra DE, De Souza CT (2012) Reversion of steatosis by SREBP-1c antisense oligonucleotide did not improve hepatic insulin action in diet-induced obesity mice. Horm Metab Res 44(12):885–890CrossRef

37.

Rector RS, Uptergrove GM, Morris EM, Borengasser SJ, Laughlin MH, Booth FW, Thyfault JP, Ibdah JA (2011) Daily exercise vs. caloric restriction for prevention of nonalcoholic fatty liver disease in the OLETF rat model. Am J Physiol Gastrointest Liver Physiol 300(5):G874–G883CrossRef

38.

Linden MA, Fletcher JA, Morris EM, Meers GM, Laughlin MH, Booth FW, Sowers JR, Ibdah JA, Thyfault JP, Rector RS (2015) Treating NAFLD in OLETF rats with vigorous-intensity interval exercise training. Med Sci Sports Exerc 47(3):556–567CrossRef

39.

Hu X, Duan Z, Hu H, Li G, Yan S, Wu J, Wang J, Yin D, Xie Q (2013) Proteomic profile of carbonylated proteins in rat liver: exercise attenuated oxidative stress may be involved in fatty liver improvement.” Proteomics 13(10–11):1755–1764CrossRef

40.

Lea W, Abbas AS, Sprecher H, Vockley J, Schulz H (2000) Long-chain acyl-CoA dehydrogenase is a key enzyme in the mitochondrial beta-oxidation of unsaturated fatty acids. Biochim Biophys Acta 1485(2–3):121–128CrossRef

41.

Oh S, Tanaka K, Warabi E, Shoda J (2013) Exercise reduces inflammation and oxidative stress in obesity-related liver diseases. Med Sci Sports Exerc 45(12) 2214–2222CrossRef

42.

Mitranun W, Deerochanawong C, Tanaka H, Suksom D (2014) Continuous vs interval training on glycemic control and macro- and microvascular reactivity in type 2 diabetic patients. Scand J Med Sci Sport 24(2):69–76CrossRef

43.

Brandauer J, Andersen MA, Kellezi H, Risis S, Frøsig C, Vienberg SG, Treebak JT (2015) AMP-activated protein kinase controls exercise training- and AICAR-induced increases in SIRT3 and MnSOD. Front Physiol 6:85CrossRef

44.

Charbonneau A, Unson CG, Lavoie J-M (2007) High-fat diet-induced hepatic steatosis reduces glucagon receptor content in rat hepatocytes: potential interaction with acute exercise. J Physiol 579(Pt 1):255–267CrossRef

45.

Charbonneau A, Melancon A, Lavoie C, Lavoie J-M (2005) Alterations in hepatic glucagon receptor density and in Gsalpha and Gialpha2 protein content with diet-induced hepatic steatosis: effects of acute exercise. Am J Physiol Endocrinol Metab 289(1)E8–E14CrossRef

46.

Charbonneau A, Couturier K, Gauthier M-S, Lavoie J-M (2005) Evidence of hepatic glucagon resistance associated with hepatic steatosis: reversal effect of training. Int J Sports Med 26(6):432–441CrossRef

47.

Berglund ED, Lustig DG, Baheza RA, Hasenour CM, Lee-young RS, Donahue EP, Lynes SE, Swift LL, Charron MJ, Damon BM, Wasserman DH (2011) Hepatic glucagon action is essential for exercise-induced reversal of mouse fatty liver. Diabetes 60(11):2720–2729CrossRef

48.

Longuet C, Sinclair EM, Maida A, Baggio LL, Maziarz M, Charron MJ, Drucker DJ (2008) The glucagon receptor is required for the adaptive metabolic response to fasting. Cell Metab 8(5):359–371CrossRef

49.

Pedersen BK, Febbraio Ma (2012) Muscles, exercise and obesity: skeletal muscle as a secretory organ. Nat Rev Endocrinol 8(8):457–465CrossRef

50.

Marra F, Bertolani C (2009) Adipokines in liver diseases. Hepatology 50(3)957–969CrossRef

51.

Raschke S, Eckel J (2013) Adipo-myokines: two sides of the same coin–mediators of inflammation and mediators of exercise. Mediators Inflamm 2013:320724CrossRef

52.

Stefan N, Häring H-U (2013) The role of hepatokines in metabolism. Nat Rev Endocrinol 9(3):144–152CrossRef

53.

Heinrichsdorff J, Olefsky JM (2012) Fetuin-A: the missing link in lipid-induced inflammation. Nat Med 18(8):1182–1183CrossRef

54.

Malin SK, Mulya A, Fealy CE, Haus JM, Pagadala MR, Scelsi AR, Huang H, Flask CA, McCullough AJ, Kirwan JP (Oct. 2013) Fetuin-A is linked to improved glucose tolerance after short-term exercise training in nonalcoholic fatty liver disease. J Appl Physiol 115(7):988–994CrossRef

55.

Haus JM, Solomon TPJ, Kelly KR, Fealy CE, Kullman EL, Scelsi AR, Lu L, Pagadala MR, McCullough AJ, Flask CA, Kirwan JP (2013) Improved hepatic lipid composition following short-term exercise in nonalcoholic fatty liver disease. J Clin Endocrinol Metab 98(7):E1181–E1188CrossRef

56.

Passos MCF, Gonçalves MC (2014) Regulation of insulin sensitivity by adiponectin and its receptors in response to physical exercise. Horm Metab Res 46(9):603–608CrossRef

57.

Park M-J, Kim D-I, Choi J-H, Heo Y-R, Park S-H (2015) New role of irisin in hepatocytes: the protective effect of hepatic steatosis in vitro. Cell Signal 27(9):1831–1839CrossRef

58.

Batirel S, Bozaykut P, Mutlu Altundag E, Kartal N, Ozer, Mantzoros CS (2014) The effect of Irisin on antioxidant system in liver. Free Radic Biol Med 75(Suppl 1):S16CrossRef

59.

Hansen J, Pedersen B, Xu G, Lehmann R, Weigert C, Plomgaard P (2016) Exercise-induced secretion of FGF21 and follistatin are blocked by pancreatic clamp and impaired in type 2 diabetes. J Clin Endocrinol Metab 101(7):2816–2825CrossRef

60.

Owen B, Mangelsdorf J, Kliewer S (2015) Tissue-specific actions of the metabolic hormones FGF15/19 and FGF21. Trends Endocrinol Metab 26(No. 1):22–29.CrossRef

61.

Xu J, Lloyd D, Hale C, Stanislaus S, Chen M, Sivits G, Chen J (2009) Fibroblast growth factor 21 reverses hepatic steatosis, increases energy expenditure, and improves insulin sensitivity in diet-induced obese mice. Diabetes 58(1)250–259.CrossRef

62.

Whitsett M, VanWagner LB (2015) Physical activity as a treatment of non-alcoholic fatty liver disease: a systematic review. World J Hepatol 7(16):2041–2052CrossRef

63.

Jordy AB, Kraakman MJ, Gardner T, Estevez E, Kammoun HL, Weir JM, Kiens B, Meikle PJ, Febbraio Ma, Henstridge DC (2015) Analysis of the liver lipidome reveals insights into the protective effect of exercise on high-fat diet-induced hepatosteatosis in mice. Am J Physiol Endocrinol Metab 308(9):E778–E791CrossRef

64.

Cuthbertson DJ, Shojaee-Moradie F, Sprung VS, Jones H, Pugh CJA, Richardson P, Kemp GJ, Barrett M, Jackson NC, Thomas EL, Bell JD, Umpleby AM (2016) Dissociation between exercise-induced reduction in liver fat and changes in hepatic and peripheral glucose homoeostasis in obese patients with non-alcoholic fatty liver disease. Clin Sci (Lond) 130(2):93–104CrossRef

65.

Hallsworth K, Thoma C, Hollingsworth KG, Cassidy S, Anstee QM, Day CP, Trenell MI (2015) Modified high-intensity interval training reduces liver fat and improves cardiac function in non-alcoholic fatty liver disease: a randomized controlled trial. Clin Sci (Lond) 129(12):1097–1105CrossRef

66.

Sanchez-Munoz V, Salas-Romero R, Del Villar-Morales A, Martinez-Coria E, Pegueros-Perez A, Franco-Sanchez JG (2013) Decrease of liver fat content by aerobic exercise or metformin therapy in overweight or obese women. Rev Invest Clin 65(4):307–317PubMed

67.

Shojaee-Moradie F, Cuthbertson DJ, Barrett M, Jackson NC, Herring R, Thomas EL, Bell J, Kemp GJ, Wright J, Umpleby AM (2016) Exercise training reduces liver fat and increases rates of VLDL Clearance but not VLDL production in NAFLD. J Clin Endocrinol Metab 101(11):4219–4228CrossRef

68.

Zhang H-J, He J, Pan L-L, Ma Z-M, Han C-K, Chen C-S, Chen Z, Han H-W, Chen S, Sun Q, Zhang J-F, Li Z-B, Yang S-Y, Li X-J, Li X-Y (2016) Effects of moderate and vigorous exercise on nonalcoholic fatty liver disease: a randomized clinical trial. JAMA Intern Med 176(8):1074–1082CrossRef

69.

Balducci S, Cardelli P, Pugliese L, D’Errico V, Haxhi J, Alessi E, Iacobini C, Menini S, Bollanti L, Conti FG, Nicolucci A, Pugliese G (2015) Volume-dependent effect of supervised exercise training on fatty liver and visceral adiposity index in subjects with type 2 diabetes The Italian Diabetes Exercise Study (IDES). Diabetes Res Clin Pract 109(2):355–363CrossRef

70.

Zelber-Sagi S, Buch A, Yeshua H, Vaisman N, Webb M, Harari G, Kis O, Fliss-Isakov N, Izkhakov E, Halpern Z, Santo E, Oren R, Shibolet O (2014) Effect of resistance training on non-alcoholic fatty-liver disease a randomized-clinical trial. World J Gastroenterol 20(15):4382–4392CrossRef

71.

Abd El-Kader SM, Al-Shreef FM, Al-Jiffri OH (2016) Biochemical parameters response to weight loss in patients with non-alcoholic steatohepatitis. Afr Health Sci 16(1):242–249CrossRef

72.

Bacchi E, Negri C, Targher G, Faccioli N, Lanza M, Zoppini G, Zanolin E, Schena F, Bonora E, Moghetti P (2013) Both resistance training and aerobic training reduce hepatic fat content in type 2 diabetic subjects with nonalcoholic fatty liver disease (the RAED2 Randomized Trial). Hepatology 58(4):1287–1295CrossRef

73.

Shamsoddini A, Sobhani V, Ghamar Chehreh ME, Alavian SM, Zaree A (2015) Effect of aerobic and resistance exercise training on liver enzymes and hepatic fat in iranian men with nonalcoholic fatty liver disease. Hepat Mon 15(10):e31434CrossRef

74.

de Piano A, de Mello MT, P de L Sanches, da Silva PL, Campos RMS, Carnier J, Corgosinho F, Foschini D, Masquio DL, Tock L, Oyama LM, da do CMPO Nascimento, Tufik S, Damaso AR (2012) Long-term effects of aerobic plus resistance training on the adipokines and neuropeptides in nonalcoholic fatty liver disease obese adolescents. Eur J Gastroenterol Hepatol 24(11):1313–1324PubMed

Title: Role of exercise in the mechanisms ameliorating hepatic steatosis in non-alcoholic fatty liver disease
Authors: J. A. Russell-Guzmán
L. Karachon
T. A. Gacitúa
A. Freundlich
C. E. Poblete-Aro
R. Rodrigo
Publication date: 01-12-2018
Publisher: Springer Milan
Published in: Sport Sciences for Health / Issue 3/2018
Print ISSN: 1824-7490
Electronic ISSN: 1825-1234
DOI: https://doi.org/10.1007/s11332-018-0459-9

At a glance: The STEP trials

Springer Medicine

Role of exercise in the mechanisms ameliorating hepatic steatosis in non-alcoholic fatty liver disease

Abstract

At a glance: The STEP trials

Springer Medicine

Abstract

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