Biomolecules & Therapeutics

  • 제33권1호
  • /
  • Pages.18-38
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  • 2025
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  • 1976-9148(pISSN)
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  • 2005-4483(eISSN)
한국응용약물학회 (The Korean Society of Applied Pharmacology)
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New Insights into AMPK, as a Potential Therapeutic Target in Metabolic Dysfunction-Associated Steatotic Liver Disease and Hepatic Fibrosis

  • Haeun An (College of Pharmacy, Ewha Womans University) ;
  • Yerin Jang (College of Pharmacy, Ewha Womans University) ;
  • Jungin Choi (College of Pharmacy, Ewha Womans University) ;
  • Juhee Hur (College of Pharmacy, Ewha Womans University) ;
  • Seojeong Kim (Graduate School of Pharmaceutical Sciences, Ewha Womans University) ;
  • Youngjoo Kwon (College of Pharmacy, Ewha Womans University)
  • 투고 : 2024.10.16
  • 심사 : 2024.12.10
  • 발행 : 2025.01.01
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초록

AMP-activated protein kinase (AMPK) activators have garnered significant attention for their potential to prevent the progression of metabolic dysfunction-associated steatotic liver disease (MASLD) into liver fibrosis and to fundamentally improve liver function. The broad spectrum of pathways regulated by AMPK activators makes them promising alternatives to conventional liver replacement therapies and the limited pharmacological treatments currently available. In this study, we aim to illustrate the newly detailed multiple mechanisms of MASLD progression based on the multiple-hit hypothesis. This model posits that impaired lipid metabolism, combined with insulin resistance and metabolic imbalance, initiates inflammatory cascades, gut dysbiosis, and the accumulation of toxic metabolites, ultimately promoting fibrosis and accelerating MASLD progression to irreversible hepatocellular carcinoma (HCC). AMPK plays a multifaceted protective role against these pathological conditions by regulating several key downstream signaling pathways. It regulates biological effectors critical to metabolic and inflammatory responses, such as SIRT1, Nrf2, mTOR, and TGF-β, through complex and interrelated mechanisms. Due to these intricate connections, AMPK's role is pivotal in managing metabolic and inflammatory disorders. In this review, we demonstrate the specific roles of AMPK and its related pathways. Several agents directly activate AMPK by binding as agonists, while some others indirectly activate AMPK by modulating upstream molecules, including adiponectin, LKB1, and the AMP: ATP ratio. As AMPK activators can target each stage of MASLD progression, the development of AMPK activators offers immense potential to expand therapeutic strategies for liver diseases such as MASH, MASLD, and liver fibrosis.

키워드

과제정보

This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (2018R1A5A2025286) and by the Bio & Medical Technology Development Program of the NRF funded by MSIT (2021M3E5E7024855).

참고문헌

  1. Abdelhamid, A. M., Youssef, M. E., Abd El-Fattah, E. E., Gobba, N. A., Gaafar, A. G. A., Girgis, S., Shata, A., Hafez, A.-M., El-Ahwany, E. and Amin, N. A. (2021a) Blunting p38 MAPKα and ERK1/2 activities by empagliflozin enhances the antifibrotic effect of metformin and augments its AMPK-induced NF-κB inactivation in mice intoxicated with carbon tetrachloride. Life Sci. 286, 120070.
  2. Abdelhamid, A. M., Youssef, M. E., Abd El-Fattah, E. E., Gobba, N. A., Gaafar, A. G. A., Girgis, S., Shata, A., Hafez, A.-M., El-Ahwany, E., Amin, N. A., Shahien, M. A., Abd-Eldayem, M. A., Abou-Elrous, M. and Saber, S. (2021b) Blunting p38 MAPKα and ERK1/2 activities by empagliflozin enhances the antifibrotic effect of metformin and augments its AMPK-induced NF-κB inactivation in mice intoxicated with carbon tetrachloride. Life Sci. 286, 120070.
  3. Alvarez-Guardia, D., Palomer, X., Coll, T., Davidson, M. M., Chan, T. O., Feldman, A. M., Laguna, J. C. and Vázquez-Carrera, M. (2010) The p65 subunit of NF-κB binds to PGC-1α, linking inflammation and metabolic disturbances in cardiac cells. Cardiovasc. Res. 87, 449-458.
  4. Alves-Bezerra, M. and Cohen, D. E. (2017) Triglyceride metabolism in the liver. Compr. Physiol. 8, 1-8.
  5. Amireddy, N., Dulam, V., Kaul, S., Pakkiri, R. and Kalivendi, S. V. (2023) The mitochondrial uncoupling effects of nitazoxanide enhances cellular autophagy and promotes the clearance of α-synuclein: potential role of AMPK-JNK pathway. Cell. Signal. 109, 110769.
  6. Ascenzi, F., De Vitis, C., Maugeri-Saccà, M., Napoli, C., Ciliberto, G. and Mancini, R. (2021) SCD1, autophagy and cancer: implications for therapy. J. Exp. Clin. Cancer Res. 40, 265.
  7. Awazawa, M., Ueki, K., Inabe, K., Yamauchi, T., Kaneko, K., Okazaki, Y., Bardeesy, N., Ohnishi, S., Nagai, R. and Kadowaki, T. (2009) Adiponectin suppresses hepatic SREBP1c expression in an AdipoR1/LKB1/AMPK dependent pathway. Biochem. Biophys. Res. Commun. 382, 51-56.
  8. Bai, X., Fu, R., Deng, J., Yang, H., Zhu, C. and Fan, D. (2024) New dawn of ginsenosides: regulating gut microbiota to treat metabolic syndrome. Phytochem. Rev. 23, 1247-1269.
  9. Barroso, W. A., Victorino, V. J., Jeremias, I. C., Petroni, R. C., Ariga, S. K. K., Salles, T. A., Barbeiro, D. F., de Lima, T. M. and de Souza, H. P. (2018) High-fat diet inhibits PGC-1α suppressive effect on NFκB signaling in hepatocytes. Eur. J. Nutr. 57, 1891-1900.
  10. Batchuluun, B., Pinkosky, S. L. and Steinberg, G. R. (2022) Lipogenesis inhibitors: therapeutic opportunities and challenges. Nat. Rev. Drug Discov. 21, 283-305.
  11. Bhattacharya, D., Basta, B., Mato, J. M., Craig, A., Fernández-Ramos, D., Lopitz-Otsoa, F., Tsvirkun, D., Hayardeny, L., Chandar, V. and Schwartz, R. E. (2021) Aramchol downregulates stearoyl CoA desaturase 1 in hepatic stellate cells to attenuate cellular fibrogenesis. JHEP Rep. 3, 100237.
  12. Bonnet, L. V., Palandri, A., Flores-Martin, J. B. and Hallak, M. E. (2024) Arginyltransferase 1 modulates p62-driven autophagy via mTORC1/AMPk signaling. Cell Commun. Signal. 22, 87.
  13. Bray, F., Laversanne, M., Sung, H., Ferlay, J., Siegel, R. L., Soerjomataram, I. and Jemal, A. (2024) Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 74, 229-263.
  14. Budi, E. H., Schaub, J. R., Decaris, M., Turner, S. and Derynck, R. (2021) TGF-β as a driver of fibrosis: physiological roles and therapeutic opportunities. J. Pathol. 254, 358-373.
  15. Burra, P., Becchetti, C. and Germani, G. (2020) NAFLD and liver transplantation: disease burden, current management and future challenges. JHEP Rep. 2, 100192.
  16. Buzzetti, E., Pinzani, M. and Tsochatzis, E. A. (2016) The multiple-hit pathogenesis of non-alcoholic fatty liver disease (NAFLD). Metabolism 65, 1038-1048.
  17. Cani, P. D., Possemiers, S., Van de Wiele, T., Guiot, Y., Everard, A., Rottier, O., Geurts, L., Naslain, D., Neyrinck, A. and Lambert, D. M. (2009) Changes in gut microbiota control inflammation in obese mice through a mechanism involving GLP-2-driven improvement of gut permeability. Gut 58, 1091-1103.
  18. Cantó, C. and Auwerx, J. (2010) AMP-activated protein kinase and its downstream transcriptional pathways. Cell. Mol. Life Sci. 67, 3407-3423.
  19. Cantó, C., Gerhart-Hines, Z., Feige, J. N., Lagouge, M., Noriega, L., Milne, J. C., Elliott, P. J., Puigserver, P. and Auwerx, J. (2009) AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity. Nature 458, 1056-1060.
  20. Chen, J., Deng, X., Liu, Y., Tan, Q., Huang, G., Che, Q., Guo, J. and Su, Z. (2020) Kupffer cells in non-alcoholic fatty liver disease: friend or foe? Int. J. Biol. Sci. 16, 2367.
  21. Chen, Z., Yu, R., Xiong, Y., Du, F. and Zhu, S. (2017) A vicious circle between insulin resistance and inflammation in nonalcoholic fatty liver disease. Lipids Health Dis. 16, 203.
  22. Cheng, D., Zhang, M., Zheng, Y., Wang, M., Gao, Y., Wang, X., Liu, X., Lv, W., Zeng, X., Belosludtsev, K. N., Su, J., Zhao, L. and Liu, J. (2024) α-Ketoglutarate prevents hyperlipidemia-induced fatty liver mitochondrial dysfunction and oxidative stress by activating the AMPK-pgc-1α/Nrf2 pathway. Redox Biol. 74, 103230.
  23. Choi, E.-J., Oh, H.-T., Lee, S.-H., Zhang, C.-S., Li, M., Kim, S.-Y., Park, S., Chang, T.-S., Lee, B.-H. and Lin, S.-C. (2024) Metabolic stress induces a double-positive feedback loop between ampk and sqstm1/P62 conferring dual activation of ampk and nfe2l2/nrf2 to synergize antioxidant defense. Autophagy 20, 2490-2510.
  24. Chopra, I., Li, H. F., Wang, H. and Webster, K. A. (2012) Phosphorylation of the insulin receptor by AMP-activated protein kinase (AMPK) promotes ligand-independent activation of the insulin signalling pathway in rodent muscle. Diabetologia 55, 783-794.
  25. Chyau, C.-C., Wang, H.-F., Zhang, W.-J., Chen, C.-C., Huang, S.-H., Chang, C.-C. and Peng, R. Y. (2020) Antrodan alleviates high-fat and high-fructose diet-induced fatty liver disease in C57BL/6 mice model via AMPK/Sirt1/SREBP-1c/PPARγ pathway. Int. J. Mol. Sci. 21, 360.
  26. Combs, T. P. and Marliss, E. B. (2014) Adiponectin signaling in the liver. Rev. Endocr. Metab. Disord. 15, 137-147.
  27. Cui, Q., Fu, S. and Li, Z. (2013) Hepatocyte growth factor inhibits TGFβ1-induced myofibroblast differentiation in tendon fibroblasts: role of AMPK signaling pathway. J. Physiol. Sci. 63, 163-170.
  28. Cui, Q., Wang, Z., Jiang, D., Qu, L., Guo, J. and Li, Z. (2011) HGF inhibits TGF-β1-induced myofibroblast differentiation and ECM deposition via MMP-2 in Achilles tendon in rat. Eur. J. Appl. Physiol. 111, 1457-1463.
  29. Cusi, K., Alkhouri, N., Harrison, S., Fouqueray, P., Moller, D., Hallakou Bozec, S., Bolze, S., Grouin, J., Jeannin Megnien, S. and Dubourg, J. (2021) Efficacy and safety of PXL770, a direct AMP kinase activator, for the treatment of non-alcoholic fatty liver disease (STAMP NAFLD): a randomised, double-blind, placebo-controlled, phase 2a study. Lancet Gastroenterol. Hepatol. 6, 889-902.
  30. Day, E. A., Ford, R. J., Smith, B. K., Houde, V. P., Stypa, S., Rehal, S., Lhotak, S., Kemp, B. E., Trigatti, B. L. and Werstuck, G. H. (2021) Salsalate reduces atherosclerosis through AMPKβ1 in mice. Mol. Metabol. 53, 101321.
  31. de Ceuninck van Capelle, C., Spit, M. and Ten Dijke, P. (2020) Current perspectives on inhibitory SMAD7 in health and disease. Crit. Rev. Biochem. Mol. Biol. 55, 691-715.
  32. Demir, M., Lang, S., Hartmann, P., Duan, Y., Martin, A., Miyamoto, Y., Bondareva, M., Zhang, X., Wang, Y. and Kasper, P. (2022) The fecal mycobiome in non-alcoholic fatty liver disease. J. Hepatol. 76, 788-799.
  33. Di Mauro, S., Scamporrino, A., Filippello, A., Di Pino, A., Scicali, R., Malaguarnera, R., Purrello, F. and Piro, S. (2021) Clinical and molecular biomarkers for diagnosis and staging of NAFLD. Int. J. Mol. Sci. 22, 11905.
  34. Din, F. V. N., Valanciute, A., Houde, V. P., Zibrova, D., Green, K. A., Sakamoto, K., Alessi, D. R. and Dunlop, M. G. (2012) Aspirin inhibits mTOR signaling, activates AMP-activated protein kinase, and induces autophagy in colorectal cancer cells. Gastroenterology 142, 1504-1515.e3.
  35. Duan, H., Wang, L., Huangfu, M. and Li, H. (2023) The impact of microbiota-derived short-chain fatty acids on macrophage activities in disease: mechanisms and therapeutic potentials. Biomed. Pharmacother. 165, 115276.
  36. Entezari, M., Hashemi, D., Taheriazam, A., Zabolian, A., Mohammadi, S., Fakhri, F., Hashemi, M., Hushmandi, K., Ashrafizadeh, M., Zarrabi, A., Ertas, Y. N., Mirzaei, S. and Samarghandian, S. (2022) AMPK signaling in diabetes mellitus, insulin resistance and diabetic complications: a pre-clinical and clinical investigation. Biomed. Pharmacother. 146, 112563.
  37. Esler, W. P. and Cohen, D. E. (2023) Pharmacologic inhibition of lipogenesis for the treatment of NAFLD. J. Hepatol. 80, 362-377.
  38. Fernández-Ramos, D., Lopitz-Otsoa, F., Delacruz-Villar, L., Bilbao, J., Pagano, M., Mosca, L., Bizkarguenaga, M., Serrano-Macia, M., Azkargorta, M. and Iruarrizaga-Lejarreta, M. (2020) Arachidyl amido cholanoic acid improves liver glucose and lipid homeostasis in nonalcoholic steatohepatitis via AMPK and mTOR regulation. World J. Gastroenterol. 26, 5101.
  39. Ferré, P., Phan, F. and Foufelle, F. (2021) SREBP-1c and lipogenesis in the liver: an update. Biochem. J. 478, 3723-3739.
  40. Flessa, C.-M., Kyrou, I., Nasiri-Ansari, N., Kaltsas, G., Papavassiliou, A. G., Kassi, E. and Randeva, H. S. (2021) Endoplasmic Reticulum stress and autophagy in the pathogenesis of non-alcoholic fatty liver disease (NAFLD): current evidence and perspectives. Curr. Obes. Rep. 10, 134-161.
  41. Fouqueray, P., Bolze, S., Dubourg, J., Hallakou-Bozec, S., Theurey, P., Grouin, J.-M., Chevalier, C., Gluais-Dagorn, P., Moller, D. E. and Cusi, K. (2021) Pharmacodynamic effects of direct AMP kinase activation in humans with insulin resistance and non-alcoholic fatty liver disease: a phase 1b study. Cell Rep. Med. 2, 100474.
  42. Fromenty, B. and Roden, M. (2023) Mitochondrial alterations in fatty liver diseases. J. Hepatol. 78, 415-429.
  43. Fulco, M., Cen, Y., Zhao, P., Hoffman, E. P., McBurney, M. W., Sauve, A. A. and Sartorelli, V. (2008) Glucose restriction inhibits skeletal myoblast differentiation by activating SIRT1 through AMPK-mediated regulation of Nampt. Dev. Cell 14, 661-673.
  44. Fullerton, M. D., Galic, S., Marcinko, K., Sikkema, S., Pulinilkunnil, T., Chen, Z.-P., O'neill, H. M., Ford, R. J., Palanivel, R. and O'brien, M. (2013) Single phosphorylation sites in Acc1 and Acc2 regulate lipid homeostasis and the insulin-sensitizing effects of metformin. Nat. Med. 19, 1649-1654.
  45. Galic, S., Loh, K., Murray-Segal, L., Steinberg, G. R., Andrews, Z. B. and Kemp, B. E. (2018) AMPK signaling to acetyl-CoA carboxylase is required for fasting- and cold-induced appetite but not thermogenesis. eLife 7, e32656.
  46. Gao, J., Ye, J., Ying, Y., Lin, H. and Luo, Z. (2018) Negative regulation of TGF-β by AMPK and implications in the treatment of associated disorders. Acta Biochim. Biophys. Sin. 50, 523-531.
  47. García-Ruiz, C. and Fernández-Checa, J. C. (2018) Mitochondrial oxidative stress and antioxidants balance in fatty liver disease. Hepatol. Commun. 2, 1425-1439.
  48. Geng, Y., Faber, K. N., de Meijer, V. E., Blokzijl, H. and Moshage, H. (2021) How does hepatic lipid accumulation lead to lipotoxicity in non-alcoholic fatty liver disease? Hepatol. Int. 15, 21-35.
  49. Ginès, P., Krag, A., Abraldes, J. G., Solà, E., Fabrellas, N. and Kamath, P. S. (2021) Liver cirrhosis. Lancet 398, 1359-1376.
  50. Gough, N. R., Xiang, X. and Mishra, L. (2021) TGF-β signaling in liver, pancreas, and gastrointestinal diseases and cancer. Gastroenterology 161, 434-452.e15.
  51. Guo, P., Kai, Q., Gao, J., Lian, Z.-q., Wu, C.-m., Wu, C.-a. and Zhu, H.-b. (2010) Cordycepin prevents hyperlipidemia in hamsters fed a high-fat diet via activation of AMP-activated protein kinase. J. Pharmacol. Sci. 113, 395-403.
  52. Gwinn, D. M., Shackelford, D. B., Egan, D. F., Mihaylova, M. M., Mery, A., Vasquez, D. S., Turk, B. E. and Shaw, R. J. (2008) AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol. Cell 30, 214-226.
  53. Hagström, H., Vessby, J., Ekstedt, M. and Shang, Y. (2024) 99% of patients with NAFLD meet MASLD criteria and natural history is therefore identical. J. Hepatol. 80, e76-e77.
  54. Hardie, D. G., Carling, D. and Gamblin, S. J. (2011) AMP-activated protein kinase: also regulated by ADP? Trends Biochem. Sci. 36, 470-477.
  55. Hardie, D. G., Ross, F. A. and Hawley, S. A. (2012) AMPK: a nutrient and energy sensor that maintains energy homeostasis. Nat. Rev. Mol. Cell Biol. 13, 251-262.
  56. Hardie, D. G., Scott, J. W., Pan, D. A. and Hudson, E. R. (2003) Management of cellular energy by the AMP-activated protein kinase system. FEBS Lett. 546, 113-120.
  57. Hata, A. and Chen, Y. G. (2016) TGF-β Signaling from receptors to Smads. Cold Spring Harb. Perspect. Biol. 8, a022061.
  58. He, C. (2022) Balancing nutrient and energy demand and supply via autophagy. Curr. Biol. 32, R684-R696.
  59. Herzig, S. and Shaw, R. J. (2018) AMPK: guardian of metabolism and mitochondrial homeostasis. Nat. Rev. Mol. Cell Biol. 19, 121-135.
  60. Hoyles, L., Fernández-Real, J.-M., Federici, M., Serino, M., Abbott, J., Charpentier, J., Heymes, C., Luque, J. L., Anthony, E. and Barton, R. H. (2018) Molecular phenomics and metagenomics of hepatic steatosis in non-diabetic obese women. Nat. Med. 24, 1070-1080.
  61. Hsu, C. L. and Schnabl, B. (2023) The gut–liver axis and gut microbiota in health and liver disease. Nat. Rev. Microbiol. 21, 719-733.
  62. Huang, D. Q., El-Serag, H. B. and Loomba, R. (2021) Global epidemiology of NAFLD-related HCC: trends, predictions, risk factors and prevention. Nat. Rev. Gastroenterol. Hepatol. 18, 223-238.
  63. Huang, S. and Czech, M. P. (2007) The GLUT4 glucose transporter. Cell Metab. 5, 237-252.
  64. Imai, S., Armstrong, C. M., Kaeberlein, M. and Guarente, L. (2000) Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase. Nature 403, 795-800.
  65. Ioannou, G. N., Subramanian, S., Chait, A., Haigh, W. G., Yeh, M. M., Farrell, G. C., Lee, S. P. and Savard, C. (2017) Cholesterol crystallization within hepatocyte lipid droplets and its role in murine NASH [S]. J. Lipid Res. 58, 1067-1079.
  66. Iwabu, M., Yamauchi, T., Okada-Iwabu, M., Sato, K., Nakagawa, T., Funata, M., Yamaguchi, M., Namiki, S., Nakayama, R., Tabata, M., Ogata, H., Kubota, N., Takamoto, I., Hayashi, Y. K., Yamauchi, N., Waki, H., Fukayama, M., Nishino, I., Tokuyama, K., Ueki, K., Oike, Y., Ishii, S., Hirose, K., Shimizu, T., Touhara, K. and Kadowaki, T. (2010) Adiponectin and AdipoR1 regulate PGC-1α and mitochondria by Ca2+ and AMPK/SIRT1. Nature 464, 1313-1319.
  67. Jager, J., Grémeaux, T., Cormont, M., Le Marchand-Brustel, Y. and Tanti, J.-F. (2007) Interleukin-1β-induced insulin resistance in adipocytes through down-regulation of insulin receptor substrate-1 expression. Endocrinology 148, 241-251.
  68. Jensen-Cody, S. O. and Potthoff, M. J. (2021) Hepatokines and metabolism: Deciphering communication from the liver. Mol. Metab. 44, 101138.
  69. Joo, M. S., Kim, W. D., Lee, K. Y., Kim, J. H., Koo, J. H. and Kim, S. G. (2016) AMPK facilitates nuclear accumulation of Nrf2 by phosphorylating at serine 550. Mol. Cell. Biol. 36, 1931-1942.
  70. Kadowaki, T., Yamauchi, T., Kubota, N., Hara, K., Ueki, K. and Tobe, K. (2006) Adiponectin and adiponectin receptors in insulin resistance, diabetes, and the metabolic syndrome. J. Clin. Invest. 116, 1784-1792.
  71. Kasper, P., Martin, A., Lang, S., Kuetting, F., Goeser, T., Demir, M. and Steffen, H.-M. (2021) NAFLD and cardiovascular diseases: a clinical review. Clin. Res. Cardiol. 110, 921-937.
  72. Kawauchi, K., Araki, K., Tobiume, K. and Tanaka, N. (2008) p53 regulates glucose metabolism through an IKK-NF-κB pathway and inhibits cell transformation. Nat. Cell Biol. 10, 611-618.
  73. Kazankov, K., Jørgensen, S. M. D., Thomsen, K. L., Møller, H. J., Vilstrup, H., George, J., Schuppan, D. and Grønbæk, H. (2019) The role of macrophages in nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Nat. Rev. Gastroenterol. Hepatol. 16, 145-159.
  74. Kazyken, D., Dame, S. G., Wang, C., Wadley, M. and Fingar, D. C. (2024) Unexpected roles for AMPK in the suppression of autophagy and the reactivation of MTORC1 signaling during prolonged amino acid deprivation. Autophagy 20, 2017-2040.
  75. Keam, S. J. (2024) Resmetirom: first approval. Drugs 84, 729-735.
  76. Khanmohammadi, S. and Kuchay, M. S. (2022) Toll-like receptors and metabolic (dysfunction)-associated fatty liver disease. Pharmacol. Res. 185, 106507.
  77. Kim, C. H. (2023) Complex regulatory effects of gut microbial short chain fatty acids on immune tolerance and autoimmunity. Cell. Mol. Immunol. 20, 341-350.
  78. Kim, D. H. (2024) Contrasting views on the role of AMPK in autophagy. BioEssays 46, 2300211.
  79. Kim, H. Y., Sakane, S., Eguileor, A., Carvalho Gontijo Weber, R., Lee, W., Liu, X., Lam, K., Ishizuka, K., Rosenthal, S. B., Diggle, K., Brenner, D. A. and Kisseleva, T. (2024) The Origin and Fate of Liver Myofibroblasts. Cell. Mol. Gastroenterol. Hepatol. 17, 93-106.
  80. Kim, J., Kim, Y. C., Fang, C., Russell, R. C., Kim, J. H., Fan, W., Liu, R., Zhong, Q. and Guan, K.-L. (2013) Differential regulation of distinct Vps34 complexes by AMPK in nutrient stress and autophagy. Cell 152, 290-303.
  81. Kim, J., Kundu, M., Viollet, B. and Guan, K.-L. (2011) AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat. Cell Biol. 13, 132-141.
  82. Kim, S. Y., Jeong, J.-M., Kim, S. J., Seo, W., Kim, M.-H., Choi, W.-M., Yoo, W., Lee, J.-H., Shim, Y.-R. and Yi, H.-S. (2017) Pro-inflammatory hepatic macrophages generate ROS through NADPH oxidase 2 via endocytosis of monomeric TLR4–MD2 complex. Nat. Commun. 8, 1-15.
  83. Kitto, L. J. and Henderson, N. C. (2021) Hepatic stellate cell regulation of liver regeneration and repair. Hepatol. Commun. 5, 358-370.
  84. Kong, L., Zhang, H., Lu, C., Shi, K., Huang, H., Zheng, Y., Wang, Y., Wang, D., Wang, H. and Huang, W. (2021) AICAR, an AMP-activated protein kinase activator, ameliorates acute pancreatitis-associated liver injury partially through Nrf2-mediated antioxidant effects and inhibition of NLRP3 inflammasome activation. Front. Pharmacol. 12, 724514.
  85. Kopczyńska, J. and Kowalczyk, M. (2024) The potential of short-chain fatty acid epigenetic regulation in chronic low-grade inflammation and obesity. Front. Immunol. 15, 1380476.
  86. Kottakis, F. and Bardeesy, N. (2012) LKB1-AMPK axis revisited. Cell Res. 22, 1617-1620.
  87. Lee, G., You, H. J., Bajaj, J. S., Joo, S. K., Yu, J., Park, S., Kang, H., Park, J. H., Kim, J. H. and Lee, D. H. (2020) Distinct signatures of gut microbiome and metabolites associated with significant fibrosis in non-obese NAFLD. Nat. Commun. 11, 4982.
  88. Lee, M. J., Park, J.-S., Jo, S. B. and Joe, Y. A. (2023) Enhancing anticancer therapy with selective autophagy inhibitors by targeting protective autophagy. Biomol. Ther. (Seoul) 31, 1-15.
  89. Li, F., Jiang, M., Ma, M., Chen, X., Zhang, Y., Zhang, Y., Yu, Y., Cui, Y., Chen, J., Zhao, H., Sun, Z. and Dong, D. (2022a) Anthelmintics nitazoxanide protects against experimental hyperlipidemia and hepatic steatosis in hamsters and mice. Acta Pharm. Sin. B 12, 1322-1338.
  90. Li, J., Chen, C., Zhang, W., Bi, J. a., Yang, G. and Li, E. (2021) Salsalate reverses metabolic disorders in a mouse model of non-alcoholic fatty liver disease through AMPK activation and caspase-6 activity inhibition. Basic Clin. Pharmacol. Toxicol. 128, 394-409.
  91. Li, M., Zhang, C.-S., Zong, Y., Feng, J.-W., Ma, T., Hu, M., Lin, Z., Li, X., Xie, C. and Wu, Y. (2019) Transient receptor potential V channels are essential for glucose sensing by aldolase and AMPK. Cell Metab. 30, 508-524.e12.
  92. Li, N.-S., Zou, J.-R., Lin, H., Ke, R., He, X.-L., Xiao, L., Huang, D., Luo, L., Lv, N. and Luo, Z. (2016) LKB1/AMPK inhibits TGF-β1 production and the TGF-β signaling pathway in breast cancer cells. Tumor Biol. 37, 8249-8258.
  93. Li, Q., Tan, J.-X., He, Y., Bai, F., Li, S.-W., Hou, Y.-W., Ji, L.-S., Gao, Y.-T., Zhang, X. and Zhou, Z.-H. (2022b) Atractylenolide III ameliorates non-alcoholic fatty liver disease by activating hepatic adiponectin receptor 1-mediated AMPK pathway. Int. J. Biol. Sci. 18, 1594.
  94. Li, W., Chang, N. and Li, L. (2022c) Heterogeneity and function of kupffer cells in liver injury. Front. Immunol. 13, 940867.
  95. Li, Y., Xu, S., Mihaylova, M. M., Zheng, B., Hou, X., Jiang, B., Park, O., Luo, Z., Lefai, E. and Shyy, J. Y.-J. (2011) AMPK phosphorylates and inhibits SREBP activity to attenuate hepatic steatosis and atherosclerosis in diet-induced insulin-resistant mice. Cell Metab. 13, 376-388.
  96. Licheva, M., Raman, B., Kraft, C. and Reggiori, F. (2022) Phosphoregulation of the autophagy machinery by kinases and phosphatases. Autophagy 18, 104-123.
  97. Lin, H., Shi, F., Jiang, S., Wang, Y., Zou, J., Ying, Y., Huang, D., Luo, L., Yan, X. and Luo, Z. (2020) Metformin attenuates trauma-induced heterotopic ossification via inhibition of Bone Morphogenetic Protein signalling. J. Cell. Mol. Med. 24, 14491-14501.
  98. Lin, H., Ying, Y., Wang, Y.-Y., Wang, G., Jiang, S.-S., Huang, D., Luo, L., Chen, Y.-G., Gerstenfeld, L. C. and Luo, Z. (2017) AMPK downregulates ALK2 via increasing the interaction between Smurf1 and Smad6, leading to inhibition of osteogenic differentiation. Biochim. Biophys. Acta Mol. Cell Res. 1864, 2369-2377.
  99. Loomba, R., Friedman, S. L. and Shulman, G. I. (2021) Mechanisms and disease consequences of nonalcoholic fatty liver disease. Cell 184, 2537-2564.
  100. Lu, J., Shi, J., Li, M., Gui, B., Fu, R., Yao, G., Duan, Z., Lv, Z., Yang, Y. and Chen, Z. (2015) Activation of AMPK by metformin inhibits TGF-β-induced collagen production in mouse renal fibroblasts. Life Sci. 127, 59-65.
  101. Luci, C., Bourinet, M., Leclère, P. S., Anty, R. and Gual, P. (2020) Chronic inflammation in non-alcoholic steatohepatitis: molecular mechanisms and therapeutic strategies. Front. Endocrinol. 11, 597648.
  102. Ma, T., Tian, X., Zhang, B., Li, M., Wang, Y., Yang, C., Wu, J., Wei, X., Qu, Q. and Yu, Y. (2022) Low-dose metformin targets the lysosomal AMPK pathway through PEN2. Nature 603, 159-165.
  103. Maestri, M., Santopaolo, F., Pompili, M., Gasbarrini, A. and Ponziani, F. R. (2023) Gut microbiota modulation in patients with non-alcoholic fatty liver disease: effects of current treatments and future strategies. Front. Nutr. 10, 1110536.
  104. Marshall, R. S. and Vierstra, R. D. (2018) Autophagy: the master of bulk and selective recycling. Annu. Rev. Plant Biol. 69, 173-208.
  105. Marti-Aguado, D., Arnouk, J., Liang, J. X., Lara-Romero, C., Behari, J., Furlan, A., Jimenez-Pastor, A., Ten-Esteve, A., Alfaro-Cervello, C. and Bauza, M. (2024) Development and validation of an image biomarker to identify metabolic dysfunction associated steatohepatitis: MR–MASH score. Liver Int. 44, 202-213.
  106. Matsusue, K., Aibara, D., Hayafuchi, R., Matsuo, K., Takiguchi, S., Gonzalez, F. J. and Yamano, S. (2014) Hepatic PPARγ and LXRα independently regulate lipid accumulation in the livers of genetically obese mice. FEBS Lett. 588, 2277-2281.
  107. Matzinger, M., Fischhuber, K., Pölöske, D., Mechtler, K. and Heiss, E. H. (2020) AMPK leads to phosphorylation of the transcription factor Nrf2, tuning transactivation of selected target genes. Redox Biol. 29, 101393.
  108. McBride, A., Ghilagaber, S., Nikolaev, A. and Hardie, D. G. (2009) The glycogen-binding domain on the AMPK β subunit allows the kinase to act as a glycogen sensor. Cell Metab. 9, 23-34.
  109. Miao, L., Targher, G., Byrne, C. D., Cao, Y.-Y. and Zheng, M.-H. (2024) Current status and future trends of the global burden of MASLD. Trends Endocrinol. Metab. 35, 697-707.
  110. Mishra, R., Cool, B. L., Laderoute, K. R., Foretz, M., Viollet, B. and Simonson, M. S. (2008) AMP-activated protein kinase inhibits transforming growth factor-β-induced Smad3-dependent transcription and myofibroblast transdifferentiation. J. Biol. Chem. 283, 10461-10469.
  111. Mladenić, K., Lenartić, M., Marinović, S., Polić, B. and Wensveen, F. M. (2024) The "Domino effect" in MASLD: the inflammatory cascade of steatohepatitis. Eur. J. Immunol. 54, 2149641.
  112. Musso, G., Gambino, R. and Cassader, M. (2013) Cholesterol metabolism and the pathogenesis of non-alcoholic steatohepatitis. Prog. Lipid Res. 52, 175-191.
  113. Nagai, S., Collins, K., Chau, L. C., Safwan, M., Rizzari, M., Yoshida, A., Abouljoud, M. S. and Moonka, D. (2019) Increased risk of death in first year after liver transplantation among patients with nonalcoholic steatohepatitis vs liver disease of other etiologies. Clin. Gastroenterol. Hepatol. 17, 2759-2768.e5.
  114. Neumann, D. (2018) Is TAK1 a direct upstream kinase of AMPK? Int. J. Mol. Sci. 19, 2412.
  115. Ni, Y., Li, J.-M., Liu, M.-K., Zhang, T.-T., Wang, D.-P., Zhou, W.-H., Hu, L.-Z. and Lv, W.-L. (2017) Pathological process of liver sinusoidal endothelial cells in liver diseases. World J. Gastroenterol. 23, 7666.
  116. Nie, T., Wang, X., Li, A., Shan, A. and Ma, J. (2024) The promotion of fatty acid β-oxidation by hesperidin via activating SIRT1/PGC1α to improve NAFLD induced by a high-fat diet. Food Funct. 15, 372-386.
  117. Oakhill, J. S., Steel, R., Chen, Z.-P., Scott, J. W., Ling, N., Tam, S. and Kemp, B. E. (2011) AMPK is a direct adenylate charge-regulated protein kinase. Science 332, 1433-1435.
  118. Olefsky, J. M. and Glass, C. K. (2010) Macrophages, inflammation, and insulin resistance. Annu. Rev. Physiol. 72, 219-246.
  119. Omidkhoda, N., Mahdiani, S., Hayes, A. W. and Karimi, G. (2023) Natural compounds against nonalcoholic fatty liver disease: a review on the involvement of the LKB1/AMPK signaling pathway. Phytother. Res. 37, 5769-5786.
  120. Ornatowski, W., Lu, Q., Yegambaram, M., Garcia, A. E., Zemskov, E. A., Maltepe, E., Fineman, J. R., Wang, T. and Black, S. M. (2020) Complex interplay between autophagy and oxidative stress in the development of pulmonary disease. Redox Biol. 36, 101679.
  121. Paik, S., Kim, J. K., Silwal, P., Sasakawa, C. and Jo, E.-K. (2021) An update on the regulatory mechanisms of NLRP3 inflammasome activation. Cell. Mol. Immunol. 18, 1141-1160.
  122. Pan, J., Yang, C., Xu, A., Zhang, H., Fan, Y., Zeng, R., Chen, L., Liu, X. and Wang, Y. (2024) Salusin-α alleviates lipid metabolism disorders via regulation of the downstream lipogenesis genes through the LKB1/AMPK pathway. Int. J. Mol. Med. 54, 73.
  123. Pang, Y., Xu, X., Xiang, X., Li, Y., Zhao, Z., Li, J., Gao, S., Liu, Q., Mai, K. and Ai, Q. (2021) High fat activates O-GlcNAcylation and affects AMPK/ACC pathway to regulate lipid metabolism. Nutrients 13, 1740.
  124. Park, I.-H., Um, J.-Y., Hong, S.-M., Cho, J.-S., Lee, S. H., Lee, S. H. and Lee, H.-M. (2014) Metformin reduces TGF-β1–induced extracellular matrix production in nasal polyp–derived fibroblasts. Otolaryngol. Head Neck Surg. 150, 148-153.
  125. Park, J.-M., Jung, C. H., Seo, M., Otto, N. M., Grunwald, D., Kim, K. H., Moriarity, B., Kim, Y.-M., Starker, C. and Nho, R. S. (2016) The ULK1 complex mediates MTORC1 signaling to the autophagy initiation machinery via binding and phosphorylating ATG14. Autophagy 12, 547-564.
  126. Park, J.-M., Lee, D.-H. and Kim, D.-H. (2023) Redefining the role of AMPK in autophagy and the energy stress response. Nat. Commun. 14, 2994.
  127. Parola, M. and Pinzani, M. (2019) Liver fibrosis: pathophysiology, pathogenetic targets and clinical issues. Mol. Aspects Med. 65, 37-55.
  128. Peng, D., Fu, M., Wang, M., Wei, Y. and Wei, X. (2022) Targeting TGF-β signal transduction for fibrosis and cancer therapy. Mol. Cancer 21, 104.
  129. Penugurti, V., Manne, R. K., Bai, L., Kant, R. and Lin, H.-K. (2024) AMPK: the energy sensor at the crossroads of aging and cancer. Semin. Cancer Biol. 106-107, 15-27.
  130. Petersen, M. C. and Shulman, G. I. (2018) Mechanisms of insulin action and insulin resistance. Physiol. Rev. 98, 2133-2223.
  131. Petsouki, E., Cabrera, S. N. S. and Heiss, E. H. (2022) AMPK and NRF2: interactive players in the same team for cellular homeostasis? Free Radic. Biol. Med. 190, 75-93.
  132. Polyzos, S. A., Chrysavgis, L., Vachliotis, I. D., Chartampilas, E. and Cholongitas, E. (2023) Nonalcoholic fatty liver disease and hepatocellular carcinoma: Insights in epidemiology, pathogenesis, imaging, prevention and therapy. In Seminars in Cancer Biology, pp. 20-35. Elsevier.
  133. Powell, E. E., Wong, V. W.-S. and Rinella, M. (2021) Non-alcoholic fatty liver disease. Lancet. 397, 2212-2224.
  134. Prakash, A. V., Park, I.-H., Park, J. W., Bae, J. P., Lee, G. S. and Kang, T. J. (2023) NLRP3 inflammasome as therapeutic targets in inflammatory diseases. Biomol. Ther. (Seoul) 31, 395-401.
  135. Rahman, M. S., Hossain, K. S., Das, S., Kundu, S., Adegoke, E. O., Rahman, M. A., Hannan, M. A., Uddin, M. J. and Pang, M.-G. (2021) Role of insulin in health and disease: an update. Int. J. Mol. Sci. 22, 6403.
  136. Ratziu, V., de Guevara, L., Safadi, R., Poordad, F., Fuster, F., Flores Figueroa, J., Arrese, M., Fracanzani, A. L., Ben Bashat, D., Lackner, K., Gorfine, T., Kadosh, S., Oren, R., Halperin, M., Hayardeny, L., Loomba, R., Friedman, S. and Sanyal, A. J. (2021) Aramchol in patients with nonalcoholic steatohepatitis: a randomized, doubleblind, placebo-controlled phase 2b trial. Nat Med. 27, 1825-1835.
  137. Rehman, K. and Akash, M. S. H. (2016) Mechanisms of inflammatory responses and development of insulin resistance: how are they interlinked? J. Biomed. Sci. 23, 87.
  138. Riazi, K., Azhari, H., Charette, J. H., Underwood, F. E., King, J. A., Afshar, E. E., Swain, M. G., Congly, S. E., Kaplan, G. G. and Shaheen, A.-A. (2022) The prevalence and incidence of NAFLD worldwide: a systematic review and meta-analysis. Lancet Gastroenterol. Hepatol. 7, 851-861.
  139. Rinella, M. E., Lazarus, J. V., Ratziu, V., Francque, S. M., Sanyal, A. J., Kanwal, F., Romero, D., Abdelmalek, M. F., Anstee, Q. M. and Arab, J. P. (2023) A multisociety Delphi consensus statement on new fatty liver disease nomenclature. Hepatology 78, 1966-1986.
  140. Rius-Pérez, S., Torres-Cuevas, I., Millán, I., Ortega, Á. L. and Pérez, S. (2020) PGC-1α, inflammation, and oxidative stress: an integrative view in metabolism. Oxid. Med. Cell. Longev. 2020, 1452696.
  141. Roach, P. J. (2011) AMPK → uLK1 → autophagy. Mol. Cell. Biol. 31, 3082-3084.
  142. Rodgers, J. T. and Puigserver, P. (2007) Fasting-dependent glucose and lipid metabolic response through hepatic sirtuin 1. Proc. Natl. Acad. Sci. U. S. A. 104, 12861-12866.
  143. Rohm, T. V., Meier, D. T., Olefsky, J. M. and Donath, M. Y. (2022) Inflammation in obesity, diabetes, and related disorders. Immunity 55, 31-55.
  144. Ruderman, N. and Prentki, M. (2004) AMP kinase and malonyl-CoA: targets for therapy of the metabolic syndrome. Nat. Rev. Drug Discov. 3, 340-351.
  145. Ruderman, N. B., Carling, D., Prentki, M. and Cacicedo, J. M. (2013) AMPK, insulin resistance, and the metabolic syndrome. J. Clin. Invest. 123, 2764-2772.
  146. Russell, R. C., Tian, Y., Yuan, H., Park, H. W., Chang, Y.-Y., Kim, J., Kim, H., Neufeld, T. P., Dillin, A. and Guan, K.-L. (2013) ULK1 induces autophagy by phosphorylating Beclin-1 and activating VPS34 lipid kinase. Nat. Cell Biol. 15, 741-750.
  147. Sadria, M. and Layton, A. T. (2021) Interactions among mTORC, AMPK and SIRT: a computational model for cell energy balance and metabolism. Cell Commun. Signal. 19, 57.
  148. Safadi, R., Konikoff, F. M., Mahamid, M., Zelber-Sagi, S., Halpern, M., Gilat, T. and Oren, R. (2014) The fatty acid-bile acid conjugate Aramchol reduces liver fat content in patients with nonalcoholic fatty liver disease. Clin. Gastroenterol. Hepatol. 12, 2085-2091.e1.
  149. Sakurai, Y., Kubota, N., Yamauchi, T. and Kadowaki, T. (2021) Role of insulin resistance in MAFLD. Int. J. Mol. Sci. 22, 4156.
  150. Salminen, A., Hyttinen, J. M. and Kaarniranta, K. (2011) AMP-activated protein kinase inhibits NF-κB signaling and inflammation: impact on healthspan and lifespan. J. Mol. Med. 89, 667-676.
  151. Samsuzzaman, M. and Kim, S. Y. (2023) Anti-fibrotic effects of DLglyceraldehyde in hepatic stellate cells via activation of ERK-JNK caspase-3 signaling axis. Biomol. Ther. (Seoul) 31, 425-433.
  152. Samuel, V. T. and Shulman, G. I. (2016) The pathogenesis of insulin resistance: integrating signaling pathways and substrate flux. J. Clin. Invest. 126, 12-22.
  153. Samuel, V. T. and Shulman, G. I. (2018) Nonalcoholic fatty liver disease as a nexus of metabolic and hepatic diseases. Cell Metab. 27, 22-41.
  154. Schmitt, D. L., Curtis, S. D., Lyons, A. C., Zhang, J.-f., Chen, M., He, C. Y., Mehta, S., Shaw, R. J. and Zhang, J. (2022) Spatial regulation of AMPK signaling revealed by a sensitive kinase activity reporter. Nat. Commun. 13, 3856.
  155. Schreurs, M., Kuipers, F. and Van Der Leij, F. R. (2010) Regulatory enzymes of mitochondrial β-oxidation as targets for treatment of the metabolic syndrome. Obes. Rev. 11, 380-388.
  156. Schultze, S. M., Hemmings, B. A., Niessen, M. and Tschopp, O. (2012) PI3K/AKT, MAPK and AMPK signalling: protein kinases in glucose homeostasis. Expert Rev. Mol. Med. 14, e1.
  157. Schwabe, R. F., Tabas, I. and Pajvani, U. B. (2020) Mechanisms of Fibrosis Development in Nonalcoholic Steatohepatitis. Gastroenterology. 158, 1913-1928.
  158. Scott, J. W., Ross, F. A., Liu, J. D. and Hardie, D. G. (2007) Regulation of AMP-activated protein kinase by a pseudosubstrate sequence on the γ subunit. EMBO J. 26, 806-815.
  159. Sharma, A., Anand, S. K., Singh, N., Dwarkanath, A., Dwivedi, U. N. and Kakkar, P. (2021) Berbamine induced activation of the SIRT1/LKB1/AMPK signaling axis attenuates the development of hepatic steatosis in high-fat diet-induced NAFLD rats. Food Funct. 12, 892-909.
  160. Shi, Y. and Massagué, J. (2003) Mechanisms of TGF-β signaling from cell membrane to the nucleus. Cell 113, 685-700.
  161. Shi, Y., Su, W., Zhang, L., Shi, C., Zhou, J., Wang, P., Wang, H., Shi, X., Wei, S. and Wang, Q. (2021) TGR5 regulates macrophage inflammation in nonalcoholic steatohepatitis by modulating NLRP3 inflammasome activation. Front. Immunol. 11, 609060.
  162. Simon, T. G., Wilechansky, R. M., Stoyanova, S., Grossman, A., Dichtel, L. E., Lauer, G. M., Miller, K. K., Hoshida, Y., Corey, K. E., Loomba, R., Chung, R. T. and Chan, A. T. (2024) Aspirin for metabolic dysfunction–associated steatotic liver disease without cirrhosis: a randomized clinical trial. JAMA 331, 920-929.
  163. Singh, V. and Ubaid, S. (2020) Role of silent information regulator 1 (SIRT1) in regulating oxidative stress and inflammation. Inflammation 43, 1589-1598.
  164. Sinha, R. A., Singh, B. K. and Yen, P. M. (2017) Reciprocal crosstalk between autophagic and endocrine signaling in metabolic homeostasis. Endocr. Rev. 38, 69-102.
  165. Smith, G. I., Shankaran, M., Yoshino, M., Schweitzer, G. G., Chondronikola, M., Beals, J. W., Okunade, A. L., Patterson, B. W., Nyangau, E. and Field, T. (2020) Insulin resistance drives hepatic de novo lipogenesis in nonalcoholic fatty liver disease. J. Clin. Invest. 130, 1453-1460.
  166. Song, M. J. and Malhi, H. (2019) The unfolded protein response and hepatic lipid metabolism in non alcoholic fatty liver disease. Pharmacol. Ther. 203, 107401.
  167. Song, N., Xu, H., Wu, S., Luo, S., Xu, J., Zhao, Q., Wang, R. and Jiang, X. (2023) Synergistic activation of AMPK by AdipoR1/2 agonist and inhibitor of EDPs–EBP interaction recover NAFLD through enhancing mitochondrial function in mice. Acta Pharm. Sin. B 13, 542-558.
  168. Song, Z., Xiaoli, A. M. and Yang, F. (2018) Regulation and metabolic significance of de novo lipogenesis in adipose tissues. Nutrients 10, 1383.
  169. Stanley, T. L., Fourman, L. T., Zheng, I., McClure, C. M., Feldpausch, M. N., Torriani, M., Corey, K. E., Chung, R. T., Lee, H. and Kleiner, D. E. (2021) Relationship of IGF-1 and IGF-binding proteins to disease severity and glycemia in nonalcoholic fatty liver disease. J. Clin. Endocrinol. Metab. 106, e520-e533.
  170. Steinberg, G. R. and Carling, D. (2019) AMP-activated protein kinase: the current landscape for drug development. Nat. Rev. Drug Discov. 18, 527-551.
  171. Steinberg, G. R. and Hardie, D. G. (2023) New insights into activation and function of the AMPK. Nat. Rev. Mol. Cell Biol. 24, 255-272.
  172. Suchankova, G., Nelson, L. E., Gerhart-Hines, Z., Kelly, M., Gauthier, M. S., Saha, A. K., Ido, Y., Puigserver, P. and Ruderman, N. B. (2009) Concurrent regulation of AMP-activated protein kinase and SIRT1 in mammalian cells. Biochem. Biophys. Res. Commun. 378, 836-841.
  173. Thakur, S., Viswanadhapalli, S., Kopp, J. B., Shi, Q., Barnes, J. L., Block, K., Gorin, Y. and Abboud, H. E. (2015) Activation of AMPactivated protein kinase prevents TGF-β1–induced epithelial-mesenchymal transition and myofibroblast activation. Am. J. Pathol. 185, 2168-2180.
  174. Tian, W., Li, W., Chen, Y., Yan, Z., Huang, X., Zhuang, H., Zhong, W., Chen, Y., Wu, W. and Lin, C. (2015) Phosphorylation of ULK1 by AMPK regulates translocation of ULK1 to mitochondria and mitophagy. FEBS Lett. 589, 1847-1854.
  175. Tian, Y., Feng, H., Han, L., Wu, L., Lv, H., Shen, B., Li, Z., Zhang, Q. and Liu, G. (2018) Magnolol alleviates inflammatory responses and lipid accumulation by AMP-activated protein kinase-dependent peroxisome proliferator-activated receptor α activation. Front. Immunol. 9, 147.
  176. Tilg, H., Adolph, T. E. and Moschen, A. R. (2021) Multiple parallel hits hypothesis in nonalcoholic fatty liver disease: revisited after a decade. Hepatology 73, 833-842.
  177. Tolman, K. G., Fonseca, V., Dalpiaz, A. and Tan, M. H. (2007) Spectrum of liver disease in type 2 diabetes and management of patients with diabetes and liver disease. Diabetes Care 30, 734-743.
  178. Townsend, L. K. and Steinberg, G. R. (2023) AMPK and the endocrine control of metabolism. Endocr. Rev. 44, 910-933.
  179. Tsuchida, T. and Friedman, S. L. (2017) Mechanisms of hepatic stellate cell activation. Nat. Rev. Gastroenterol. Hepatol. 14, 397-411.
  180. Tyczyńska, M., Hunek, G., Szczasny, M., Brachet, A., Januszewski, J., Forma, A., Portincasa, P., Flieger, J. and Baj, J. (2024) Supplementation of micro-and macronutrients—a role of nutritional status in non-alcoholic fatty liver disease. Int. J. Mol. Sci. 25, 4916.
  181. Tzatsos, A. and Tsichlis, P. N. (2007) Energy depletion inhibits phosphatidylinositol 3-kinase/Akt signaling and induces apoptosis via AMP-activated protein kinase-dependent phosphorylation of IRS-1 at Ser-794. J. Biol. Chem. 282, 18069-18082.
  182. Vargas, J. N. S., Hamasaki, M., Kawabata, T., Youle, R. J. and Yoshimori, T. (2023) The mechanisms and roles of selective autophagy in mammals. Nat. Rev. Mol. Cell Biol. 24, 167-185.
  183. Varghese, B., Chianese, U., Capasso, L., Sian, V., Bontempo, P., Conte, M., Benedetti, R., Altucci, L., Carafa, V. and Nebbioso, A. (2023) SIRT1 activation promotes energy homeostasis and reprograms liver cancer metabolism. J. Transl. Med. 21, 627.
  184. Viollet, B., Horman, S., Leclerc, J., Lantier, L., Foretz, M., Billaud, M., Giri, S. and Andreelli, F. (2010) AMPK inhibition in health and disease. Crit. Rev. Biochem. Mol. Biol. 45, 276-295.
  185. Wang, M., Han, Z., Fan, B., Qu, K., Zhang, W., Li, W., Li, J., Li, L., Li, J., Li, H., Wu, S., Wang, D. and Zhu, H. (2024) Discovery of oral AMP-activated protein kinase activators for treating hyperlipidemia. J. Med. Chem. 67, 7870-7890.
  186. Wang, X. and Jia, J. (2023) Magnolol improves Alzheimer's diseaselike pathologies and cognitive decline by promoting autophagy through activation of the AMPK/mTOR/ULK1 pathway. Biomed. Pharmacother. 161, 114473.
  187. Wang, Y., Yu, W., Li, S., Guo, D., He, J. and Wang, Y. (2022) Acetyl CoA carboxylases and diseases. Front. Oncol. 12, 836058.
  188. Wei, J., Zhang, Y., Yu, T.-Y., Sadre-Bazzaz, K., Rudolph, M. J., Amodeo, G. A., Symington, L. S., Walz, T. and Tong, L. (2016) A unified molecular mechanism for the regulation of acetyl-CoA carboxylase by phosphorylation. Cell Discov. 2, 1-12.
  189. Wei, S., Wang, L., Evans, P. C. and Xu, S. (2024) NAFLD and NASH: etiology, targets and emerging therapies. Drug Discov. Today 29, 103910.
  190. White Jr, A. C. (2004) Nitazoxanide: a new broad spectrum antiparasitic agent. Expert Rev. Anti Infect. Ther. 2, 43-49.
  191. Woods, A., Dickerson, K., Heath, R., Hong, S.-P., Momcilovic, M., Johnstone, S. R., Carlson, M. and Carling, D. (2005) Ca2+/calmodulin-dependent protein kinase kinase-β acts upstream of AMP-activated protein kinase in mammalian cells. Cell Metab. 2, 21-33.
  192. Woods, A., Johnstone, S. R., Dickerson, K., Leiper, F. C., Fryer, L. G., Neumann, D., Schlattner, U., Wallimann, T., Carlson, M. and Carling, D. (2003) LKB1 is the upstream kinase in the AMP-activated protein kinase cascade. Curr. Biol. 13, 2004-2008.
  193. Wu, J., Puppala, D., Feng, X., Monetti, M., Lapworth, A. L. and Geoghegan, K. F. (2013) Chemoproteomic analysis of intertissue and interspecies isoform diversity of AMP-activated protein kinase (AMPK). J. Biol. Chem. 288, 35904-35912.
  194. Wu, M., Zhang, C., Xie, M., Zhen, Y., Lai, B., Liu, J., Qiao, L., Liu, S. and Shi, D. (2021) Compartmentally scavenging hepatic oxidants through AMPK/SIRT3-PGC1α axis improves mitochondrial biogenesis and glucose catabolism. Free Radic. Biol. Med. 168, 117-128.
  195. Xanthopoulos, A., Starling, R. C., Kitai, T. and Triposkiadis, F. (2019) Heart failure and liver disease: cardiohepatic interactions. JACC Heart Fail. 7, 87-97.
  196. Xiao, B., Heath, R., Saiu, P., Leiper, F. C., Leone, P., Jing, C., Walker, P. A., Haire, L., Eccleston, J. F. and Davis, C. T. (2007) Structural basis for AMP binding to mammalian AMP-activated protein kinase. Nature 449, 496-500.
  197. Xiao, B., Sanders, M. J., Underwood, E., Heath, R., Mayer, F. V., Carmena, D., Jing, C., Walker, P. A., Eccleston, J. F. and Haire, L. F. (2011) Structure of mammalian AMPK and its regulation by ADP. Nature 472, 230-233.
  198. Xiao, H., Ma, X., Feng, W., Fu, Y., Lu, Z., Xu, M., Shen, Q., Zhu, Y. and Zhang, Y. (2010) Metformin attenuates cardiac fibrosis by inhibiting the TGFβ1–Smad3 signalling pathway. Cardiovasc. Res. 87, 504-513.
  199. Xu, G.-X., Wei, S., Yu, C., Zhao, S.-Q., Yang, W.-J., Feng, Y.-H., Pan, C., Yang, K.-X. and Ma, Y. (2023) Activation of Kupffer cells in NAFLD and NASH: mechanisms and therapeutic interventions. Front. Cell Dev. Biol. 11, 1199519.
  200. Xu, X., Poulsen, K. L., Wu, L., Liu, S., Miyata, T., Song, Q., Wei, Q., Zhao, C., Lin, C. and Yang, J. (2022) Targeted therapeutics and novel signaling pathways in non-alcohol-associated fatty liver/steatohepatitis (NAFL/NASH). Signal Transduct. Target. Ther. 7, 287.
  201. Yamauchi, T., Kamon, J., Minokoshi, Y. a., Ito, Y., Waki, H., Uchida, S., Yamashita, S., Noda, M., Kita, S. and Ueki, K. (2002) Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase. Nat. Med. 8, 1288-1295.
  202. Yamauchi, T., Nio, Y., Maki, T., Kobayashi, M., Takazawa, T., Iwabu, M., Okada-Iwabu, M., Kawamoto, S., Kubota, N., Kubota, T., Ito, Y., Kamon, J., Tsuchida, A., Kumagai, K., Kozono, H., Hada, Y., Ogata, H., Tokuyama, K., Tsunoda, M., Ide, T., Murakami, K., Awazawa, M., Takamoto, I., Froguel, P., Hara, K., Tobe, K., Nagai, R., Ueki, K. and Kadowaki, T. (2007) Targeted disruption of AdipoR1 and AdipoR2 causes abrogation of adiponectin binding and metabolic actions. Nat. Med. 13, 332-339.
  203. Yan, Y., Zhou, X. E., Xu, H. E. and Melcher, K. (2018) Structure and physiological regulation of AMPK. Int. J. Mol. Sci. 19, 3534.
  204. Yang, S., Duan, Z., Zhang, S., Fan, C., Zhu, C., Fu, R., Ma, X. and Fan, D. (2023) Ginsenoside Rh4 improves hepatic lipid metabolism and inflammation in a model of NAFLD by targeting the gut liver axis and modulating the FXR signaling pathway. Foods 12, 2492.
  205. Ying, Y., Ueta, T., Jiang, S., Lin, H., Wang, Y., Vavvas, D., Wen, R., Chen, Y.-G. and Luo, Z. (2017) Metformin inhibits ALK1-mediated angiogenesis via activation of AMPK. Oncotarget 8, 32794.
  206. Yu, X., Feng, M., Guo, J., Wang, H., Yu, J., Zhang, A., Wu, J., Han, Y., Sun, Z., Liao, Y. and Zhao, Q. (2024) MLKL promotes hepatocarcinogenesis through inhibition of AMPK-mediated autophagy. Cell Death Differ. 31, 1085-1098.
  207. Yuan, J., Chen, C., Cui, J., Lu, J., Yan, C., Wei, X., Zhao, X., Li, N., Li, S. and Xue, G. (2019) Fatty liver disease caused by high-alcohol producing Klebsiella pneumoniae. Cell Metab. 30, 675-688. e677.
  208. Zhang, C.-S., Hawley, S. A., Zong, Y., Li, M., Wang, Z., Gray, A., Ma, T., Cui, J., Feng, J.-W. and Zhu, M. (2017) Fructose-1, 6-bisphosphate and aldolase mediate glucose sensing by AMPK. Nature 548, 112-116.
  209. Zhang, D., Wang, W., Sun, X., Xu, D., Wang, C., Zhang, Q., Wang, H., Luo, W., Chen, Y. and Chen, H. (2016) AMPK regulates autophagy by phosphorylating BECN1 at threonine 388. Autophagy 12, 1447-1459.
  210. Zhang, J., Lv, W., Liu, X., Sun, Z., Zeng, M., Kang, J., Zhang, Q., Liu, F., Ma, S., Su, J., Cao, K. and Liu, J. (2024) Ginsenoside Rh4 prevents endothelial dysfunction as a novel AMPK activator. Br. J. Pharmacol. 181, 3346-3363.
  211. Zhang, J., Wang, E., Zhang, L. and Zhou, B. (2021) PSPH induces cell autophagy and promotes cell proliferation and invasion in the hepatocellular carcinoma cell line Huh7 via the AMPK/mTOR/ULK1 signaling pathway. Cell Biol. Int. 45, 305-319.
  212. Zhang, S., Peng, X., Yang, S., Li, X., Huang, M., Wei, S., Liu, J., He, G., Zheng, H. and Yang, L. (2022) The regulation, function, and role of lipophagy, a form of selective autophagy, in metabolic disorders. Cell Death Dis. 13, 132.
  213. Zhang, Y.-L., Guo, H., Zhang, C.-S., Lin, S.-Y., Yin, Z., Peng, Y., Luo, H., Shi, Y., Lian, G. and Zhang, C. (2013) AMP as a low-energy charge signal autonomously initiates assembly of AXIN-AMPKLKB1 complex for AMPK activation. Cell Metab. 18, 546-555.
  214. Zhang, Y., Zhang, L., Zhao, Y., He, J., Zhang, Y. and Zhang, X. (2023) PGC-1α inhibits M2 macrophage polarization and alleviates liver fibrosis following hepatic ischemia reperfusion injury. Cell Death Discov. 9, 337.
  215. Zhang, Y. E. (2009) Non-Smad pathways in TGF-β signaling. Cell Res. 19, 128-139.
  216. Zhao, H., Wu, L., Yan, G., Chen, Y., Zhou, M., Wu, Y. and Li, Y. (2021) Inflammation and tumor progression: signaling pathways and targeted intervention. Signal Transduct. Target. Ther. 6, 263.
  217. Zhao, P., Sun, X., Chaggan, C., Liao, Z., In Wong, K., He, F., Singh, S., Loomba, R., Karin, M. and Witztum, J. L. (2020) An AMPK–caspase-6 axis controls liver damage in nonalcoholic steatohepatitis. Science 367, 652-660.
  218. Zhao, Y., Sun, N., Song, X., Zhu, J., Wang, T., Wang, Z., Yu, Y., Ren, J., Chen, H., Zhan, T., Tian, J., Ma, C., Huang, J., Wang, J., Zhang, Y. and Yang, B. (2023) A novel small molecule AdipoR2 agonist ameliorates experimental hepatic steatosis in hamsters and mice. Free Radic. Biol. Med. 203, 69-85.
  219. Zhou, L., Deepa, S. S., Etzler, J. C., Ryu, J., Mao, X., Fang, Q., Liu, D. D., Torres, J. M., Jia, W. and Lechleiter, J. D. (2009) Adiponectin activates AMP-activated protein kinase in muscle cells via APPL1/LKB1-dependent and phospholipase C/Ca2+/Ca2+/calmodulindependent protein kinase kinase-dependent pathways. J. Biol. Chem. 284, 22426-22435.
  220. Zhou, Y., Zhong, L., Yu, S., Shen, W., Cai, C. and Yu, H. (2020) Inhibition of stearoyl-coenzyme A desaturase 1 ameliorates hepatic steatosis by inducing AMPK-mediated lipophagy. Aging (Albany N.Y.) 12, 7350.
  221. Zimmermann, K., Baldinger, J., Mayerhofer, B., Atanasov, A. G., Dirsch, V. M. and Heiss, E. H. (2015) Activated AMPK boosts the Nrf2/HO-1 signaling axis—a role for the unfolded protein response. Free Radic. Biol. Med. 88, 417-426.
  222. Zong, Y., Li, H., Liao, P., Chen, L., Pan, Y., Zheng, Y., Zhang, C., Liu, D., Zheng, M. and Gao, J. (2024) Mitochondrial dysfunction: mechanisms and advances in therapy. Signal Transduct. Target. Ther. 9, 124.