Document Type : Research Paper

Authors

1 Ph.D. Student of Exercise Physiology, Department of Sport Sciences, Shahrekord University, Shahrekord, Iran

2 Associate Professor of Exercise Physiology, Department of Sport Sciences, Shahrekord University, Shahrekord, Iran

3 Professor of Embryology, Royan Institute for Biotechnology, Isfahan, Iran

Abstract

The aim of this study was to investigate the effects of eight weeks of high intensity interval training (HIIT) on gene expression of PPARγ and liver TG in rats with nonalcoholic fatty liver disease. In this experimental study, thirty male Wistar rats were randomly divided into two groups. The first group (20 rats), consumed 16 weeks a high-fat diet with the aim of create a fatty liver, and the second group (control), (10 rats), consumed standard diet during this period of time. After confirmation of fatty liver by measuring the serum level of ALT enzyme in the first group, they were randomly divided into two groups of NAFLD and NAFLD+HIIT (each group of 10 rats), the NAFLD+HIIT group performed progressive exercise training for eight weeks, according to percentage of maximum speed (75-90 percent) and the NAFLD and control groups only took their diet and did not participate in any exercise. After eight weeks of exercise training, expression of PPARγ and TG level were measured. Data analysis showed a significant increase in PPARγ expression in the NAFLD+HIIT group compared to the NAFLD group (P=0.001). Liver triglyceride in NAFLD+HIIT group had a significant decrease (P=0.001). On the other hand, the mean weight of rats in the NAFLD + HIIT group did not change significantly (P= 0.054), but the mean weight of control and NAFLD groups increased significantly during this period (P=0.001). It seems that high intensity interval training by increasing in expression of PPARγ and its effect on the regulation of the expression of effective genes in fat metabolism, independent of weight loss, can reduce liver TG and improves fatty liver disease.

Keywords

Main Subjects

  1. Anderson EL, Howe LD, Jones HE, Higgins JP, Lawlor DA, Fraser A. The prevalence of non-alcoholic fatty liver disease in children and adolescents: a systematic review and meta-analysis. PloS one. 2015;10(10):0140908.
  2. Okumura T. Role of lipid droplet proteins in liver steatosis. J Physiol Biochem. 2011;67(4):629-36.
  3. Reue K. A thematic review series: lipid droplet storage and metabolism: from yeast to man. J Lipid Res. 2011;52(11):1865-8.
  4. Musso G, Gambino R, Cassader M. Recent insights into hepatic lipid metabolism in non-alcoholic fatty liver disease (NAFLD). Progress in Lipid Research. 2009;48(1):1-26.
  5. Gimm T, Wiese M, Teschemacher B, Deggerich A, Schödel J, Knaup KX, et al. Hypoxia-inducible protein 2 is a novel lipid droplet protein and a specific target gene of hypoxia-inducible factor-1. The FASEB Journal. 2010;24(11):4443-58.
  6. Uchimura K, Nakamuta M, Enjoji M, Irie T, Sugimoto R, Muta T, et al. Activation of retinoic X receptor and peroxisome proliferator–activated receptor‐γ inhibits nitric oxide and tumor necrosis factor‐α production in rat Kupffer cells. Hepatology. 2001;33(1):91-9.
  7. Wu T, Gao X, Chen M, Van Dam R. Long‐term effectiveness of diet‐plus‐exercise interventions vs. diet‐only interventions for weight loss: a meta‐analysis. Obesity Reviews. 2009;10(3):313-23.
  8. Lalloyer F, Staels B. Fibrates, glitazones, and peroxisome proliferator–activated receptors. Arteriosclerosis, Thrombosis, and Vascular Biology. 2010;30(5):894-9.
  9. Maeda N, Takahashi M, Funahashi T, Kihara S, Nishizawa H, Kishida K, et al. PPARγ ligands increase expression and plasma concentrations of adiponectin, an adipose-derived protein. Diabetes. 2001;50(9):2094-9.
  10. Wang X, Huang G, Mei S, Qian J, Ji J, Zhang J. Over-expression of C/EBP-α induces apoptosis in cultured rat hepatic stellate cells depending on p53 and peroxisome proliferator-activated receptor-γ. Biochemical and Biophysical Research Communications. 2009;380(2):286-91.
  11. Bouhlel MA, Derudas B, Rigamonti E, Dièvart R, Brozek J, Haulon S, et al. PPARγ activation primes human monocytes into alternative M2 macrophages with anti-inflammatory properties. Cell Metabolism. 2007;6(2):137-43.
  12. Kanda T, Brown JD, Orasanu G, Vogel S, Gonzalez FJ, Sartoretto J, et al. PPARγ in the endothelium regulates metabolic responses to high-fat diet in mice. The Journal of Clinical Investigation. 2008;119(1): 110-24.
  13. Murase T, Haramizu S, Shimotoyodome A, Nagasawa A, Tokimitsu I. Green tea extract improves endurance capacity and increases muscle lipid oxidation in mice. American Journal of Physiology-Regulatory, Integrative and Comparative Physiology. 2005;288(3):708-15.
  14. Boström P, Wu J, Jedrychowski MP, Korde A, Ye L, Lo JC, et al. A PGC1-α-dependent myokine that drives brown-fat-like development of white fat and thermogenesis. Nature. 2012;481(7382):463-8.
  15. Linden MA, Sheldon RD, Meers GM, Ortinau LC, Morris EM, Booth FW, et al. Aerobic exercise training in the treatment of non‐alcoholic fatty liver disease related fibrosis. The Journal of Physiology. 2016;594(18):5271-84.
  16. Marcinko K, Sikkema SR, Samaan MC, Kemp BE, Fullerton MD, Steinberg GR. High intensity interval training improves liver and adipose tissue insulin sensitivity. Molecular Metabolism. 2015;4(12):903-15.
  17. Nevill M, Holmyard D, Hall G, Allsop P, Van Oosterhout A, Burrin J, et al. Growth hormone responses to treadmill sprinting in sprint-and endurance-trained athletes. European Journal of Applied Physiology and Occupational Physiology. 1996;72(5-6):460-7.
  18. Van der Windt DJ, Sud V, Zhang H, Tsung A, Huang H. The Effects of physical exercise on fatty liver disease. Gene Expression. 2018;18(2):89-101.
  19. Oh S, So R, Shida T, Matsuo T, Kim B, Akiyama K, et al. High-intensity aerobic exercise improves both hepatic fat content and stiffness in sedentary obese men with nonalcoholic fatty liver disease. Scientific Reports. 2017;7:43029.
  20. Saris W, Schrauwen P. Substrate oxidation differences between high-and low-intensity exercise are compensated over 24 hours in obese men. International Journal of Obesity. 2004;28(6):759-65.
  21. Van der Heijden GJ, Wang ZJ, Chu ZD, Sauer PJ, Haymond MW, Rodriguez LM, et al. A 12‐week aerobic exercise program reduces hepatic fat accumulation and insulin resistance in obese, Hispanic adolescents. Obesity. 2010;18(2):384-90.
  22. Laforgia J, Withers RT, Gore CJ. Effects of exercise intensity and duration on the excess post-exercise oxygen consumption. Journal of Sports Sciences. 2006;24(12):1247-64.
  23. Karstoft K, Pedersen BK. Skeletal muscle as a gene regulatory endocrine organ. Current Opinion in Clinical Nutrition and Metabolic Care. 2016;19(4):270-5.
  24. Mobasher M, Sasani P, Al-e-Davood SJ, Aramesh K, Larijani B. Revision of the guideline for ethical use of animals. Journal of Medical Ethics and History of Medicine. 2012;5(1):70-111. (In Persian).
  25. Cho J, Koh Y, Han J, Kim D, Kim T, Kang H. Adiponectin mediates the additive effects of combining daily exercise with caloric restriction for treatment of non-alcoholic fatty liver. International Journal of Obesity. 2016;40(11):1760.
  26. Clark JM, Brancati FL, Diehl AM. The prevalence and etiology of elevated aminotransferase levels in the United States. The American Journal of Gastroenterology. 2003;98(5):960-7.
  27. Giboney PT. Mildly elevated liver transaminase levels in the asymptomatic patient. Am Fam Physician. 2005;71(6):1105-10.
  28. Leandro CG, Levada AC, Hirabara SM, Manhães-de-Castro R. A program of moderate physical training for Wistar rats based on maximal oxygen consumption. Journal of Strength and Conditioning Research. 2007;21(3):751-6.
  29. Rezaei R, Nurshahi M, Bigdeli M, Khodagholi F, haghparast A. Effect of eight weeks continues and HIIT exercises on VEGF-A and VEGFR-2 levels in stratum, hippocampus and cortex of wistar rat brain. Physiology of Exercise and Physical Activity. 2015;8(2):1213-21. (In Persian).
  30. Rahimi M, Shekarforoush S, Asgari AR, Khoshbaten A, Rajabi H, Bazgir B, et al. The effect of high intensity interval training on cardioprotection against ischemia-reperfusion injury in wistar rats. EXCLI Journal. 2015;14:237-46.
  31. Smith-Ryan AE, Melvin MN, Wingfield HL. High-intensity interval training: Modulating interval duration in overweight/obese men. The Physician and Sports Medicine. 2015;43(2):107-13.
  32. Mattijssen F, Georgiadi A, Andasarie T, Szalowska E, Zota A, Krones-Herzig A, et al. Hypoxia-inducible lipid droplet-associated (HILPDA) is a novel peroxisome proliferator-activated receptor (PPAR) target involved in hepatic triglyceride secretion. Journal of Biological Chemistry. 2014;289(28):19279-93.
  33. Shen Y, Xu X, Yue K, Xu G. Effect of different exercise protocols on metabolic profiles and fatty acid metabolism in skeletal muscle in high-fat diet-fed rats. Obesity (Silver Spring). 2015;23(5):1000-6.
  34. Suk M, Shin Y. Effect of high-intensity exercise and high-fat diet on lipid metabolism in the liver of rats. Journal of Exercise Nutrition & Biochemistry. 2015;19(4):289.
  35. Löfgren L, Forsberg G-B, Ståhlman M. The BUME method: a new rapid and simple chloroform-free method for total lipid extraction of animal tissue. Scientific Reports. 2016;6:(1).
  36. Sohrabipour S, Sharifi MR, Talebi A, Sharifi M, Soltani N. GABA dramatically improves glucose tolerance in streptozotocin-induced diabetic rats fed with high-fat diet. European Journal of Pharmacology. 2018;826:75-84.
  37. Nan Y-M, Fu N, Wu W-J, Liang B-L, Wang R-Q, Zhao S-X, et al. Rosiglitazone prevents nutritional fibrosis and steatohepatitis in mice. Scandinavian Journal of Gastroenterology. 2009;44(3):358-65.
  38. Ahn HY, Kim HH, Hwang J-Y, Park C, Cho BY, Park YJ. Effects of pioglitazone on nonalcoholic fatty liver disease in the absence of constitutive androstane receptor expression. PPAR Research. 2018; Article ID 9568269, 10 pages.
  39. Dutchak PA, Katafuchi T, Bookout AL, Choi JH, Ruth TY, Mangelsdorf DJ, et al. Fibroblast growth factor-21 regulates PPARγ activity and the antidiabetic actions of thiazolidinediones. Cell. 2012;148(3):556-67.
  40. He W, Barak Y, Hevener A, Olson P, Liao D, Le J, et al. Adipose-specific peroxisome proliferator-activated receptor γ knockout causes insulin resistance in fat and liver but not in muscle. Proceedings of the National Academy of Sciences. 2003;100(26):15712-7.
  41. Maillard F, Pereira B, Boisseau N. Effect of high-intensity interval training on total, abdominal and visceral fat mass: A meta-analysis. Sports Medicine. 2018;48(2):269-88.
  42. Hallsworth K, Thoma C, Hollingsworth KG, Cassidy S, Anstee QM, Day CP, et al. Modified high-intensity interval training reduces liver fat and improves cardiac function in non-alcoholic fatty liver disease: A randomised controlled trial. Clinical Science. 2015;129:1097-105.
  43. Charbonneau A, Melancon A, Lavoie C, Lavoie J-M. Alterations in hepatic glucagon receptor density and in Gsα and Giα2 protein content with diet-induced hepatic steatosis: effects of acute exercise. American Journal of Physiology-Endocrinology and Metabolism. 2005;289(1):8-14.
  44. Verdijk LB, Gleeson BG, Jonkers RA, Meijer K, Savelberg HH, Dendale P, et al. Skeletal muscle hypertrophy following resistance training is accompanied by a fiber type–specific increase in satellite cell content in elderly men. Journals of Gerontology Series A: Biomedical Sciences and Medical Sciences. 2009;64(3):332-9.
  45. Zheng H, Li S, Ma L, Cheng L, Deng C, Chen Z, et al. A novel agonist of PPAR-γ based on barbituric acid alleviates the development of non-alcoholic fatty liver disease by regulating adipocytokine expression and preventing insulin resistance. European Journal of Pharmacology. 2011;659(2-3):244-51.
  46. Zhu Y-X, Zhang M-L, Zhong Y, Wang C, Jia W-P. Modulation effect of peroxisome proliferator-activated receptor agonists on lipid droplet proteins in liver. Journal of Diabetes Research. 2016; Article ID 8315454, 9 pages.
  47. Satoh H, Ide N, Kagawa Y, Maeda T. Hepatic steatosis with relation to increased expression of peroxisome proliferator-activated receptor-γ in insulin resistant mice. Biological and Pharmaceutical Bulletin. 2013;36(4):616-23.
  48. Nan Y-M, Han F, Kong L-B, Zhao S-X, Wang R-Q, Wu W-J, et al. Adenovirus-mediated peroxisome proliferator activated receptor gamma overexpression prevents nutritional fibrotic steatohepatitis in mice. Scandinavian Journal of Gastroenterology. 2011;46(3):358-69.
  49. Moreno M, Lombardi A, Silvestri E, Senese R, Cioffi F, Goglia F, et al. PPARs: nuclear receptors controlled by, and controlling, nutrient handling through nuclear and cytosolic signaling. PPAR Research. 2010; Article ID 435689, 10 pages.
  50. Aibara D, Matsusue K, Matsuo K, Takiguchi S, Gonzalez FJ, Yamano S. Expression of hepatic fat-specific protein 27 depends on the specific etiology of fatty liver. Biological and Pharmaceutical Bulletin. 2013;36(11):1766-72.
  51. Matsusue K. A physiological role for fat specific protein 27/cell death-inducing DFF45-like effector C in adipose and liver. Biological and Pharmaceutical Bulletin. 2010;33(3):346-50.
  52. Xu X, Park JG, So JS, Lee AH. Transcriptional activation of Fsp27 by the liver‐enriched transcription factor CREBH promotes lipid droplet growth and hepatic steatosis. Hepatology. 2015;61(3):857-69.
  53. Gentile C, Wang D, Pfaffenbach K, Cox R, Wei Y, Pagliassotti MJ. Fatty acids regulate CREBh via transcriptional mechanisms that are dependent on proteasome activity and insulin. Molecular and cellular biochemistry. 2010;344(1-2):99-107.
  54. Kim H, Mendez R, Zheng Z, Chang L, Cai J, Zhang R, et al. Liver-enriched transcription factor CREBH interacts with peroxisome proliferator-activated receptor α to regulate metabolic hormone FGF21. Endocrinology. 2014;155(3):769-82.
  55. Yu J, Zhang S, Chu ES, Go MY, Lau RH, Zhao J, et al. Peroxisome proliferator-activated receptors gamma reverses hepatic nutritional fibrosis in mice and suppresses activation of hepatic stellate cells in vitro. The International Journal of Biochemistry & Cell Biology. 2010;42(6):948-57.
  56. Wang Z, Xu J-P, Zheng Y-C, Chen W, Sun Y-W, Wu Z-Y, et al. Peroxisome proliferator-activated receptor gamma inhibits hepatic fibrosis in rats. Hepatobiliary & Pancreatic Diseases International. 2011;10(1):64-71.