Exercise Training Activates AMPK to Improve Metabolic-Associated Fatty Liver Disease: Research Progress

Authors

  • Bu Qiao School of Physical Education, Southwest University, Chongqing 400715, China
  • Jie Liu Hospital of Southwest University, Chongqing 400715, China

Keywords:

AMPK, Exercise, Metabolic-Associated Fatty Liver Disease

Abstract

Metabolic-associated fatty liver disease (MAFLD) is a metabolic disorder characterized by excessive hepatic lipid accumulation and is closely associated with insulin resistance, chronic low-grade inflammation, and mitochondrial dysfunction. Exercise training is a key non-pharmacological strategy that improves the hepatic metabolic milieu and may slow disease progression, yet the underlying molecular mechanisms remain incompletely clarified. This review aims to synthesize, from the perspective of energy metabolism regulation, the potential mechanisms by which exercise ameliorates MAFLD through activation of AMP-activated protein kinase (AMPK), thereby providing a theoretical basis for optimizing exercise-based interventions. A literature review approach was adopted. Systematic searches were conducted in major English-language academic databases, including Web of Science and PubMed, using keywords related to exercise training, MAFLD, and AMPK. Representative recent basic and clinical studies were screened and integrated to summarize relevant signaling pathways and physiological outcomes. The evidence indicates that exercise-induced AMPK activation suppresses de novo lipogenesis while promoting fatty acid oxidation, thereby reducing intrahepatic lipid deposition. Exercise may also improve mitochondrial function and enhance mitophagy, lowering oxidative stress and modulating inflammation-related signaling to attenuate chronic hepatic inflammation. Collectively, AMPK serves as a central regulatory node linking exercise stimuli to coordinated restoration of metabolic and inflammatory homeostasis in MAFLD. Future well-designed human studies and multidimensional evidence are warranted to clarify the pathway-specific effects of different exercise prescription components on AMPK signaling networks

References

Alboraie, M., Fouad, Y., & Eslam, M. (n.d.). Letter to the editor: MAFLD versus MASLD–which is more appropriate from a global perspective? Hepatology, 10.1097/HEP.886. https://doi.org/10.1097/HEP.0000000000000886

Babu, A. F., Csader, S., Lok, J., Gómez-Gallego, C., Hanhineva, K., El-Nezami, H., & Schwab, U. (2021). Positive effects of exercise intervention without weight loss and dietary changes in NAFLD-related clinical parameters: A systematic review and meta-analysis. Nutrients, 13(9), 3135. https://doi.org/10.3390/nu13093135

Banerjee, A., Das, D., Mukherjee, S., & Maji, B. K. (2024). Comprehensive study of the interplay between immunological and metabolic factors in hepatic steatosis. International Immunopharmacology, 133, 112091. https://doi.org/10.1016/j.intimp.2024.112091

Belew, G. D., & Jones, J. G. (2022). De novo lipogenesis in non‐alcoholic fatty liver disease: Quantification with stable isotope tracers. European Journal of Clinical Investigation, 52(3), e13733. https://doi.org/10.1111/eci.13733

Cacicedo, J. M., Yagihashi, N., Keaney, J. F., Ruderman, N. B., & Ido, Y. (2004). AMPK inhibits fatty acid-induced increases in NF-κB transactivation in cultured human umbilical vein endothelial cells. Biochemical and Biophysical Research Communications, 324(4), 1204–1209. https://doi.org/10.1016/j.bbrc.2004.09.177

Chan, K. E., Koh, T. J. L., Tang, A. S. P., Quek, J., Yong, J. N., Tay, P., Tan, D. J. H., Lim, W. H., Lin, S. Y., Huang, D., Chan, M., Khoo, C. M., Chew, N. W. S., Kaewdech, A., Chamroonkul, N., Dan, Y. Y., Noureddin, M., Muthiah, M., Eslam, M., & Ng, C. H. (2022). Global prevalence and clinical characteristics of metabolic-associated fatty liver disease: A meta-analysis and systematic review of 10 739 607 individuals. Journal of Clinical Endocrinology and Metabolism, 107(9), 2691–2700. https://doi.org/10.1210/clinem/dgac321

Chen, L. (2023). From metabolic dysfunction-associated fatty liver disease to metabolic dysfunction-associated steatotic liver disease: Controversy and consensus. World Journal of Hepatology, 15(12), 1253–1257. https://doi.org/10.4254/wjh.v15.i12.1253

Craige, S. M., Mammel, R. K., Amiri, N., Willoughby, O. S., & Drake, J. C. (2024). Interplay of ROS, mitochondrial quality, and exercise in aging: Potential role of spatially discrete signaling. Redox Biology, 77, 103371. https://doi.org/10.1016/j.redox.2024.103371

Day, C. P., & James, O. F. (1998). Steatohepatitis: A tale of two “hits”? Gastroenterology, 114(4), 842–845. https://doi.org/10.1016/S0016-5085(98)70599-2

Diniz, T. A., Aquino Júnior, J. C. J., Mosele, F. C., Cabral-Santos, C., Lima Junior, E. A. de, Teixeira, A. A. de S., Lira, F. S., & Rosa Neto, J. C. (2019). Exercise-induced AMPK activation and IL-6 muscle production are disturbed in adiponectin knockout mice. Cytokine, 119, 71–80. https://doi.org/10.1016/j.cyto.2019.03.009

Diniz, T. A., De Lima Junior, E. A., Teixeira, A. A., Biondo, L. A., Da Rocha, L. A. F., Valadão, I. C., Silveira, L. S., Cabral-Santos, C., De Souza, C. O., & Rosa Neto, J. C. (2021). Aerobic training improves NAFLD markers and insulin resistance through AMPK-PPAR-α signaling in obese mice. Life Sciences, 266, 118868. https://doi.org/10.1016/j.lfs.2020.118868

Drake, J. C., Wilson, R. J., Laker, R. C., Guan, Y., Spaulding, H. R., Nichenko, A. S., Shen, W., Shang, H., Dorn, M. V., Huang, K., Zhang, M., Bandara, A. B., Brisendine, M. H., Kashatus, J. A., Sharma, P. R., Young, A., Gautam, J., Cao, R., Wallrabe, H., … Yan, Z. (2021). Mitochondria-localized AMPK responds to local energetics and contributes to exercise and energetic stress-induced mitophagy. Proceedings of the National Academy of Sciences, 118(37), e2025932118. https://doi.org/10.1073/pnas.2025932118

Eslam, M., Newsome, P. N., Sarin, S. K., Anstee, Q. M., Targher, G., Romero-Gomez, M., Zelber-Sagi, S., Wai-Sun Wong, V., Dufour, J.-F., Schattenberg, J. M., Kawaguchi, T., Arrese, M., Valenti, L., Shiha, G., Tiribelli, C., Yki-Järvinen, H., Fan, J.-G., Grønbæk, H., Yilmaz, Y., … George, J. (2020). A new definition for metabolic dysfunction-associated fatty liver disease: An international expert consensus statement. Journal of Hepatology, 73(1), 202–209. https://doi.org/10.1016/j.jhep.2020.03.039

Eslam, M., Sanyal, A. J., George, J., & International Consensus Panel. (2020). MAFLD: A consensus-driven proposed nomenclature for metabolic associated fatty liver disease. Gastroenterology, 158(7), 1999-2014.e1. https://doi.org/10.1053/j.gastro.2019.11.312

Estes, C., Anstee, Q. M., Arias-Loste, M. T., Bantel, H., Bellentani, S., Caballeria, J., Colombo, M., Craxi, A., Crespo, J., Day, C. P., Eguchi, Y., Geier, A., Kondili, L. A., Kroy, D. C., Lazarus, J. V., Loomba, R., Manns, M. P., Marchesini, G., Nakajima, A., … Razavi, H. (2018). Modeling NAFLD disease burden in china, france, germany, italy, japan, spain, united kingdom, and united states for the period 2016-2030. Journal of Hepatology, 69(4), 896–904. https://doi.org/10.1016/j.jhep.2018.05.036

Fang, C., Pan, J., Qu, N., Lei, Y., Han, J., Zhang, J., & Han, D. (2022). The AMPK pathway in fatty liver disease. Frontiers in Physiology, 13, 970292. https://doi.org/10.3389/fphys.2022.970292

Gofton, C., Upendran, Y., Zheng, M.-H., & George, J. (2023). MAFLD: How is it different from NAFLD? Clinical and Molecular Hepatology, 29(Suppl), S17–S31. https://doi.org/10.3350/cmh.2022.0367

Jäger, S., Handschin, C., St.-Pierre, J., & Spiegelman, B. M. (2007). AMP-activated protein kinase (AMPK) action in skeletal muscle via direct phosphorylation of PGC-1α. Proceedings of the National Academy of Sciences, 104(29), 12017–12022. https://doi.org/10.1073/pnas.0705070104

Jin, T., Zhang, Y., Botchway, B. O. A., Huang, M., Lu, Q., & Liu, X. (2023). Quercetin activates the Sestrin2/AMPK/SIRT1 axis to improve amyotrophic lateral sclerosis. Biomedicine & Pharmacotherapy, 161, 114515. https://doi.org/10.1016/j.biopha.2023.114515

Khalafi, M., Mohebbi, H., Symonds, M. E., Karimi, P., Akbari, A., Tabari, E., Faridnia, M., & Moghaddami, K. (2020). The impact of moderate-intensity continuous or high-intensity interval training on adipogenesis and browning of subcutaneous adipose tissue in obese male rats. Nutrients, 12(4), 925. https://www.mdpi.com/2072-6643/12/4/925

Kim, W., Li, M., Jin, H., Yang, H., Türkez, H., Uhlén, M., Zhang, C., & Mardinoglu, A. (2023). Characterization of an in vitro steatosis model simulating activated de novo lipogenesis in MAFLD patients. iScience, 26(10), 107727. https://doi.org/10.1016/j.isci.2023.107727

Lin, J.-Y., Kuo, W.-W., Baskaran, R., Kuo, C.-H., Chen, Y.-A., Chen, W. S.-T., Ho, T.-J., Day, C. H., Mahalakshmi, B., & Huang, C.-Y. (2020). Swimming exercise stimulates IGF1/PI3K/akt and AMPK/SIRT1/PGC1α survival signaling to suppress apoptosis and inflammation in aging hippocampus. Aging (Albany NY), 12(8), 6852. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7202519/

Liu, Y., Cheng, Y., Xiang, N., Wang, Z., Li, S., Gong, L., & Wang, X. (2023). Aerobic exercise improves BKCa channel-mediated vasodilation in diabetic vascular smooth muscle via AMPK/Nrf2/HO-1 pathway. Acta Diabetologica, 61(4), 425–434. https://doi.org/10.1007/s00592-023-02210-z

Nan, Y., An, J., Bao, J., Chen, H., Chen, Y., Ding, H., Dou, X., Duan, Z., Fan, J., Gao, Y., Han, T., Han, Y., Hu, P., Huang, Yan, Huang, Yuan, Jia, J., Jiang, J., Jiang, Y., Li, Jie, … Qiao, Liang. (2021). The Chinese society of hepatology position statement on the redefinition of fatty liver disease. Journal of Hepatology, 75(2), 454–461. https://doi.org/10.1016/j.jhep.2021.05.003

Nassir, F. (2022). NAFLD: Mechanisms, treatments, and biomarkers. Biomolecules, 12(6), 824. https://doi.org/10.3390/biom12060824

Pafili, K., & Roden, M. (2021). Nonalcoholic fatty liver disease (NAFLD) from pathogenesis to treatment concepts in humans. Molecular Metabolism, 50, 101122. https://doi.org/10.1016/j.molmet.2020.101122

Pan, Z., Al-Busafi, S. A., Abdulla, M., Fouad, Y., Sebastiani, G., & Eslam, M. (2024). MAFLD identifies patients with significant hepatic fibrosis better than MASLD. Hepatology International. https://doi.org/10.1007/s12072-024-10673-7

Pan, Z., Derbala, M., AlNaamani, K., Ghazinian, H., Fan, J.-G., & Eslam, M. (2024). MAFLD criteria are better than MASLD criteria at predicting the risk of chronic kidney disease. Annals of Hepatology, 101512. https://doi.org/10.1016/j.aohep.2024.101512

Polyzos, S. A., Kountouras, J., & Mantzoros, C. S. (2019). Obesity and nonalcoholic fatty liver disease: From pathophysiology to therapeutics. Metabolism Clinical and Experimental, 92, 82–97. https://doi.org/10.1016/j.metabol.2018.11.014

Rinella, M. E., Lazarus, J. V., Ratziu, V., Francque, S. M., Sanyal, A. J., Kanwal, F., Romero, D., Abdelmalek, M. F., Anstee, Q. M., & Arab, J. P. (2023). A multisociety delphi consensus statement on new fatty liver disease nomenclature. Hepatology, 78(6), 1966–1986. https://journals.lww.com/hep/fulltext/2023/12000/a_multisociety_delphi_consensus_statement_on_new.28.aspx

Spaulding, H. R., & Yan, Z. (2022). AMPK and the adaptation to exercise. Annual Review of Physiology, 84(1), 209–227. https://doi.org/10.1146/annurev-physiol-060721-095517

Steinberg, G. R., & Hardie, D. G. (2023). New insights into activation and function of the AMPK. Nature Reviews Molecular Cell Biology, 24(4), 255–272. https://doi.org/10.1038/s41580-022-00547-x

Stine, J. G., DiJoseph, K., Pattison, Z., Harrington, A., Chinchilli, V. M., Schmitz, K. H., & Loomba, R. (2023). Exercise training is associated with treatment response in liver fat content by magnetic resonance imaging independent of clinically significant body weight loss in patients with nonalcoholic fatty liver disease: A systematic review and meta-analysis. American Journal of Gastroenterology, 118(7), 1204–1213. https://doi.org/10.14309/ajg.0000000000002098

Tarantino, G., Savastano, S., & Colao, A. (2010). Hepatic steatosis, low-grade chronic inflammation and hormone/growth factor/adipokine imbalance. World Journal of Gastroenterology: WJG, 16(38), 4773. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2955246/

Targher, G. (2020). Concordance between MAFLD and NAFLD diagnostic criteria in ‘real-world’ data. Liver International: Official Journal of the International Association for the Study of the Liver, 40(11), 2879–2880. https://doi.org/10.1111/liv.14623

Thyfault, J. P., & Rector, R. S. (2020). Exercise combats hepatic steatosis: Potential mechanisms and clinical implications. Diabetes, 69(4), 517–524. https://doi.org/10.2337/dbi18-0043

Tian, C., Huang, R., & Xiang, M. (2024). SIRT1: Harnessing multiple pathways to hinder NAFLD. Pharmacological Research, 203, 107155. https://doi.org/10.1016/j.phrs.2024.107155

Tilg, H., Adolph, T. E., & Moschen, A. R. (2021). Multiple parallel hits hypothesis in nonalcoholic fatty liver disease: Revisited after a decade. Hepatology, 73(2), 833–842. https://doi.org/10.1002/hep.31518

Wang, L., Yi, J., Guo, J., & Ren, X. (2023). Weigh change across adulthood is related to the presence of NAFLD: Results from NHANES III. Journal of Translational Medicine, 21(1), 142. https://doi.org/10.1186/s12967-023-04007-8

Wojtaszewski, J. F. P., Mourtzakis, M., Hillig, T., Saltin, B., & Pilegaard, H. (2002). Dissociation of AMPK activity and ACCbeta phosphorylation in human muscle during prolonged exercise. Biochemical and Biophysical Research Communications, 298(3), 309–316. https://doi.org/10.1016/s0006-291x(02)02465-8

Yang, Y., Liu, Y., Wang, Y., Chao, Y., Zhang, J., Jia, Y., Tie, J., & Hu, D. (2022). Regulation of SIRT1 and its roles in inflammation. Frontiers in Immunology, 13, 831168. https://doi.org/10.3389/fimmu.2022.831168

Zhang, X., Chen, K., Yin, S., Qian, M., & Liu, C. (2023). Association of leisure sedentary behavior and physical activity with the risk of nonalcoholic fatty liver disease: A two-sample mendelian randomization study. Frontiers in Nutrition, 10, 1158810. https://doi.org/10.3389/fnut.2023.1158810

Zou, Y.-Y., Tang, X., Chen, Z.-L., Liu, B., Zheng, L., Song, M.-Y., Xiao, Q., Zhou, Z.-Q., Peng, X.-Y., & Tang, C.-F. (2023). Exercise intervention improves mitochondrial quality in non-alcoholic fatty liver disease zebrafish. Frontiers in Endocrinology, 14, 1162485. https://doi.org/10.3389/fendo.2023.1162485

Downloads

Published

2026-02-08

How to Cite

Bu Qiao, & Jie Liu. (2026). Exercise Training Activates AMPK to Improve Metabolic-Associated Fatty Liver Disease: Research Progress . International Journal of Education and Humanities, 6(2), 300–311. Retrieved from https://i-jeh.com/index.php/ijeh/article/view/446