Document Type : Original Article

Authors

1 PhD Candidate, Department of Physical Education and Sports Sciences, Aliabad Katoul Branch, Islamic Azad University, Aliabad Katoul, Iran

2 Assistant Professor, Department of Physical Education and Sports Sciences, Aliabad Katoul Branch, Islamic Azad University, Aliabad Katoul, Iran

3 Assistant Professor of Sports Physiology, Department of Physical Education, Gorgan Branch, Islamic Azad University, Gorgan, Iran

10.30476/smsj.2024.99771.1434

Abstract

Introduction: Defective lipophagy is associated with metabolic disorders. This study investigated the effect of four weeks of aerobic exercise in a fasted state on hepatic unc-51 like autophagy activating kinase 1 (ULK1) in male rats with non-alcoholic fatty liver disease (NAFLD).
Methods: In this experimental research, 30 male Wistar rats with an NAFLD model were randomly divided into control groups: fasting, 3-day training, 5-day training, fasting + 3-day training, and fasting + 5-day training. Unlike other rats that had 24-hour access to food, the fasting groups received the same amount of nutrition during 10 hours. Continuous running was done for four weeks with 3 and 5 sessions per week and in two conditions of feeding and fasting. Statistical analysis was done with SPSS software Version 26 using one-way variance analysis and Bonferroni test with a significance level of (P≤0.05).
Results: A significant increase in the expression of the ULK1 gene was observed in the fasting, fasting + 3-day training, and fasting + 5-day training groups compared to the control and 3-day training groups (P<0.05). The increase of ULK1 in the fasting group was higher than in the 3-day- and 5-day training groups (P<0.05). Also, the increase of ULK1 in the fasting + 3-day training and fasting + 5-day training groups was significantly higher than the 5-day training group (P<0.05).
Conclusion: Fasting and exercise in the fasting state increase lipophagy and improve NAFLD.

Keywords

  1. Mohammadi F, Ghalavand A, Delaramnasab M. Effect of circuit resistance training and L-carnitine supplementation on body composition and liver function in men with non-alcoholic fatty liver disease. Jundishapur Journal of Chronic Disease Care. 2019;8(4).
  2. Davoodi M, Moosavi H, Nikbakht M. The effect of eight weeks selected aerobic exercise on liver parenchyma and liver enzymes (AST, ALT) of fat liver patients. 2012.
  3. Sveinbjornsson G, Ulfarsson MO, Thorolfsdottir RB, Jonsson BA, Einarsson E, Gunnlaugsson G, et al. Multiomics study of nonalcoholic fatty liver disease. Nat Genet. 2022;54(11):1652-63.
  4. Stefan N, Cusi K. A global view of the interplay between non-alcoholic fatty liver disease and diabetes. Lancet Diabetes Endocrinol. 2022;10(4):284-96.
  5. Smith GI, Shankaran M, Yoshino M, Schweitzer GG, Chondronikola M, Beals JW, et al. Insulin resistance drives hepatic de novo lipogenesis in nonalcoholic fatty liver disease. J Clin Invest. 2020;130(3):1453-60.
  6. Wallace M, Metallo CM. Tracing insights into de novo lipogenesis in liver and adipose tissues. Semin Cell Dev Biol. 2020;108:65-71.
  7. Carotti S, Aquilano K, Zalfa F, Ruggiero S, Valentini F, Zingariello M, et al. Lipophagy Impairment Is Associated With Disease Progression in NAFLD. Front Physiol. 2020;11:850.
  8. Cingolani F, Czaja MJ. Regulation and Functions of Autophagic Lipolysis. Trends Endocrinol Metab. 2016;27(10):696-705.
  9. Rong Z, Zheng K, Chen J, Jin X. Function and regulation of ULK1: From physiology to pathology. Gene. 2022;840:146772.
  10. Zhang S, Peng X, Yang S, Li X, Huang M, Wei S, et al. The regulation, function, and role of lipophagy, a form of selective autophagy, in metabolic disorders. Cell Death Dis. 2022;13(2):132.
  11. Zachari M, Ganley IG. The mammalian ULK1 complex and autophagy initiation. Essays Biochem. 2017;61(6):585-96.
  12. Zhang Z, Yao Z, Chen Y, Qian L, Jiang S, Zhou J, et al. Lipophagy and liver disease: New perspectives to better understanding and therapy. Biomed Pharmacother. 2018;97:339-48.
  13. Grumati P, Bonaldo P. Autophagy in skeletal muscle homeostasis and in muscular dystrophies. Cells. 2012;1(3):325-45.
  14. Yao J, Meng M, Yang S, Li F, Anderson RM, Liu C, et al. Effect of aerobic and resistance exercise on liver enzyme and blood lipids in Chinese patients with nonalcoholic fatty liver disease: a randomized controlled trial. Int J Clin Exp Med. 2018;11(5):4867-74.
  15. Su P, Chen JG, Tang DH. Exercise against nonalcoholic fatty liver disease: Possible role and mechanism of lipophagy. Life Sci. 2023;327:121837.
  16. Gao Y, Zhang W, Zeng LQ, Bai H, Li J, Zhou J, et al. Exercise and dietary intervention ameliorate high-fat diet-induced NAFLD and liver aging by inducing lipophagy. Redox Biol. 2020;36:101635.
  17. Eng JM, Estall JL. Diet-Induced Models of Non-Alcoholic Fatty Liver Disease: Food for Thought on Sugar, Fat, and Cholesterol. Cells. 2021;10(7).
  18. Alex S, Boss A, Heerschap A, Kersten S. Exercise training improves liver steatosis in mice. Nutr Metab (Lond). 2015;12:29.
  19. Moller AB, Vendelbo MH, Christensen B, Clasen BF, Bak AM, Jorgensen JO, et al. Physical exercise increases autophagic signaling through ULK1 in human skeletal muscle. J Appl Physiol (1985). 2015;118(8):971-9.
  20. Laker RC, Drake JC, Wilson RJ, Lira VA, Lewellen BM, Ryall KA, et al. Ampk phosphorylation of Ulk1 is required for targeting of mitochondria to lysosomes in exercise-induced mitophagy. Nat Commun. 2017;8(1):548.
  21. Kim J, Kundu M, Viollet B, Guan KL. AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat Cell Biol. 2011;13(2):132-41.
  22. Ruderman NB, Park H, Kaushik VK, Dean D, Constant S, Prentki M, et al. AMPK as a metabolic switch in rat muscle, liver and adipose tissue after exercise. Acta Physiol Scand. 2003;178(4):435-42.
  23. Ismail I, Keating SE, Baker MK, Johnson NA. A systematic review and meta-analysis of the effect of aerobic vs. resistance exercise training on visceral fat. Obes Rev. 2012;13(1):68-91.
  24. Ross R, Soni S, Houle SA. Negative Energy Balance Induced by Exercise or Diet: Effects on Visceral Adipose Tissue and Liver Fat. Nutrients. 2020;12(4).
  25. Bansal S, Vachher M, Arora T, Kumar B, Burman A. Visceral fat: A key mediator of NAFLD development and progression. Human Nutrition & Metabolism. 2023:200210.
  26. Casagrande BP, de Souza DV, Ribeiro DA, Medeiros A, Pisani LP, Estadella D. Hepatic inflammation precedes steatosis and is mediated by visceral fat accumulation. J Endocrinol. 2020;245(3):369-80.
  27. Ismaiel A, Jaaouani A, Leucuta DC, Popa SL, Dumitrascu DL. The Visceral Adiposity Index in Non-Alcoholic Fatty Liver Disease and Liver Fibrosis-Systematic Review and Meta-Analysis. Biomedicines. 2021;9(12).
  28. Luo Q, Wei R, Cai Y, Zhao Q, Liu Y, Liu WJ. Efficacy of Off-Label Therapy for Non-alcoholic Fatty Liver Disease in Improving Non-invasive and Invasive Biomarkers: A Systematic Review and Network Meta-Analysis of Randomized Controlled Trials. Front Med (Lausanne). 2022;9:793203.
  29. Perdomo CM, Fruhbeck G, Escalada J. Impact of Nutritional Changes on Nonalcoholic Fatty Liver Disease. Nutrients. 2019;11(3).
  30. Jokar M, Ghalavand A. The effect of twelve weeks of aerobic interval training on liver complications and cardiovascular risk factors in men with type 2 diabetes. Razi Journal of Medical Sciences. 2022;29(3):26-36.
  31. Liu GY, Sabatini DM. Author Correction: mTOR at the nexus of nutrition, growth, ageing and disease. Nat Rev Mol Cell Biol. 2020;21(4):246.
  32. Abdelbasset WK, Elsayed SH, Nambi G, Alrawaili SM, Elnegamy TE, Khalil MA, et al. Effect of Moderate-Intensity Aerobic Exercise on Hepatic Fat Content and Visceral Lipids in Hepatic Patients with Diabesity: A Single-Blinded Randomised Controlled Trial. Evid Based Complement Alternat Med. 2020;2020:1923575.
  33. Babu AF, Csader S, Lok J, Gomez-Gallego C, Hanhineva K, El-Nezami H, et al. Positive Effects of Exercise Intervention without Weight Loss and Dietary Changes in NAFLD-Related Clinical Parameters: A Systematic Review and Meta-Analysis. Nutrients. 2021;13(9).
  34. Nozaki Y, Petersen MC, Zhang D, Vatner DF, Perry RJ, Abulizi A, et al. Metabolic control analysis of hepatic glycogen synthesis in vivo. Proc Natl Acad Sci U S A. 2020;117(14):8166-76.
  35. Xia Q, Huang X, Huang J, Zheng Y, March ME, Li J, et al. The Role of Autophagy in Skeletal Muscle Diseases. Front Physiol. 2021;12:638983.
  36. Takahashi H, Kotani K, Tanaka K, Egucih Y, Anzai K. Therapeutic Approaches to Nonalcoholic Fatty Liver Disease: Exercise Intervention and Related Mechanisms. Front Endocrinol (Lausanne). 2018;9:588.
  37. Medrano M, Labayen I, Ruiz JR, Rodriguez G, Breidenassel C, Castillo M, et al. Cardiorespiratory fitness, waist circumference and liver enzyme levels in European adolescents: The HELENA cross-sectional study. J Sci Med Sport. 2017;20(10):932-6.
  38. Lu Q, Wang PS, Yang L. Golgi-associated Rab GTPases implicated in autophagy. Cell Biosci. 2021;11(1):35.
  39. da Rocha AL, Pinto AP, Bedo BLS, Morais GP, Oliveira LC, Carolino ROG, et al. Exercise alters the circadian rhythm of REV-ERB-alpha and downregulates autophagy-related genes in peripheral and central tissues. Sci Rep. 2022;12(1):20006.
  40. Zou L, Liao M, Zhen Y, Zhu S, Chen X, Zhang J, et al. Autophagy and beyond: Unraveling the complexity of UNC-51-like kinase 1 (ULK1) from biological functions to therapeutic implications. Acta Pharm Sin B. 2022;12(10):3743-82.
  41. Mizushima N. The role of the Atg1/ULK1 complex in autophagy regulation. Curr Opin Cell Biol. 2010;22(2):132-9.