Skip to main content
SpringerLink
Log in

Magnesium Supplementation Stimulates Autophagy to Reduce Lipid Accumulation in Hepatocytes via the AMPK/mTOR Pathway

  • Published:
Biological Trace Element Research Aims and scope Submit manuscript

Abstract

Metabolic-associated fatty liver disease (MAFLD) (previously known as nonalcoholic fatty liver disease (NAFLD)) is a disease with high worldwide prevalence, but with limited available therapeutic interventions. Autophagy is a cell survival mechanism for clearing excess lipids in hepatocytes and affects the occurrence and development of MAFLD. In addition, some studies have shown that magnesium deficiency is common in patients with obesity and metabolic syndrome. Magnesium supplementation can effectively improve metabolism-related diseases such as obesity and fatty liver. Our study successfully constructed a cellular model of MAFLD by 1 mM free fatty acid (FFA) intervention in LO2 cells for 24 h, and there was an increase in lipid accumulation in hepatocytes after FFA intervention. Magnesium supplementation was shown to reduce lipid deposition in hepatocytes induced by FFA, and Western blotting (WB) analysis showed that magnesium supplementation could downregulate the expression of Fasn and SREBP1 and increase the expression of LPL, suggesting that magnesium can reduce lipid accumulation by reducing lipid synthesis and increasing lipid oxidation. Magnesium supplementation could affect cellular lipid metabolism by activating the AMPK/mTOR pathway to stimulate autophagy. Our results identified a relationship between magnesium and lipid accumulation in hepatocytes and showed that magnesium supplementation reduced lipid deposition in hepatocytes by activating autophagy by activating the AMPK-mTOR pathway.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

Data availability

The authors state the availability of necessary data from the corresponding author upon reasonable request.

References

  1. Arab J, Arrese M, Trauner M (2018) Recent insights into the pathogenesis of nonalcoholic fatty liver disease. Annu Rev Pathol 13:321–350. https://doi.org/10.1146/annurev-pathol-020117-043617

    Article  CAS  PubMed  Google Scholar 

  2. Adams L, Lymp J, St Sauver J, Sanderson S, Lindor K, Feldstein A, Angulo P (2005) The natural history of nonalcoholic fatty liver disease: a population-based cohort study. Gastroenterology 129:113–121. https://doi.org/10.1053/j.gastro.2005.04.014

    Article  PubMed  Google Scholar 

  3. White D, Kanwal F, El-Serag H (2012) Association between nonalcoholic fatty liver disease and risk for hepatocellular cancer, based on systematic review. Clin Gastroenterol Hepatol : the Official Clin practice J American Gastroenterol Ass 10:1342-1359.e1342. https://doi.org/10.1016/j.cgh.2012.10.001

    Article  Google Scholar 

  4. Eslam M, Newsome PN, Sarin SK, Anstee QM, Targher G, Romero-Gomez M, Zelber-Sagi S, Wai-Sun Wong V, Dufour JF, Schattenberg JM, Kawaguchi T, Arrese M, Valenti L, Shiha G, Tiribelli C, Yki-Jarvinen H, Fan JG, Gronbaek H, Yilmaz Y, Cortez-Pinto H, Oliveira CP, Bedossa P, Adams LA, Zheng MH, Fouad Y, Chan WK, Mendez-Sanchez N, Ahn SH, Castera L, Bugianesi E, Ratziu V, George J (2020) A new definition for metabolic dysfunction-associated fatty liver disease: an international expert consensus statement. J Hepatol 73:202–209. https://doi.org/10.1016/j.jhep.2020.03.039

    Article  PubMed  Google Scholar 

  5. Eslam M, Sarin SK, Wong VW, Fan JG, Kawaguchi T, Ahn SH, Zheng MH, Shiha G, Yilmaz Y, Gani R, Alam S, Dan YY, Kao JH, Hamid S, Cua IH, Chan WK, Payawal D, Tan SS, Tanwandee T, Adams LA, Kumar M, Omata M, George J (2020) The Asian Pacific Association for the Study of the Liver clinical practice guidelines for the diagnosis and management of metabolic associated fatty liver disease. Hepatol Int 14:889–919. https://doi.org/10.1007/s12072-020-10094-2

    Article  PubMed  Google Scholar 

  6. Huang DQ, El-Serag HB, Loomba R (2021) Global epidemiology of NAFLD-related HCC: trends, predictions, risk factors and prevention. Nat Rev Gastroenterol Hepatol 18:223–238. https://doi.org/10.1038/s41575-020-00381-6

    Article  PubMed  Google Scholar 

  7. Elin RJ (1994) Magnesium: the fifth but forgotten electrolyte. Am J Clin Pathol 102:616–622. https://doi.org/10.1093/ajcp/102.5.616

    Article  CAS  PubMed  Google Scholar 

  8. Flatman PW (1984) Magnesium transport across cell membranes. J Membr Biol 80:1–14. https://doi.org/10.1007/BF01868686

    Article  CAS  PubMed  Google Scholar 

  9. Hartwig A (2001) Role of magnesium in genomic stability. Mutat Res 475:113–121. https://doi.org/10.1016/s0027-5107(01)00074-4

    Article  CAS  PubMed  Google Scholar 

  10. Piuri G, Zocchi M, Della Porta M, Ficara V, Manoni M, Zuccotti GV, Pinotti L, Maier JA, Cazzola R (2021) Magnesium in obesity, metabolic syndrome, and type 2 diabetes. Nutrients 13(2):320. https://doi.org/10.3390/nu13020320

  11. Lu L, Chen C, Yang K, Zhu J, Xun P, Shikany JM, He K (2020) Magnesium intake is inversely associated with risk of obesity in a 30-year prospective follow-up study among American young adults. Eur J Nutr 59:3745–3753. https://doi.org/10.1007/s00394-020-02206-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Ravn HB, Korsholm TL, Falk E (2001) Oral magnesium supplementation induces favorable antiatherogenic changes in ApoE-deficient mice. Arterioscler Thromb Vasc Biol 21:858–862. https://doi.org/10.1161/01.atv.21.5.858

    Article  CAS  PubMed  Google Scholar 

  13. Yue J, Jin S, Gu S, Sun R, Liang Q (2019) High concentration magnesium inhibits extracellular matrix calcification and protects articular cartilage via Erk/autophagy pathway. J Cell Physiol 234:23190–23201. https://doi.org/10.1002/jcp.28885

    Article  CAS  PubMed  Google Scholar 

  14. Brunt EM, Wong VW, Nobili V, Day CP, Sookoian S, Maher JJ, Bugianesi E, Sirlin CB, Neuschwander-Tetri BA, Rinella ME (2015) Nonalcoholic fatty liver disease. Nat Rev Dis Primers 1:15080. https://doi.org/10.1038/nrdp.2015.80

    Article  PubMed  Google Scholar 

  15. Martin S, Parton RG (2006) Lipid droplets: a unified view of a dynamic organelle. Nat Rev Mol Cell Biol 7:373–378. https://doi.org/10.1038/nrm1912

  16. Scorletti E, Carr RM (2022) A new perspective on NAFLD: focusing on lipid droplets. J Hepatol 76:934–945. https://doi.org/10.1016/j.jhep.2021.11.009

    Article  CAS  PubMed  Google Scholar 

  17. Zechner R, Strauss JG, Haemmerle G, Lass A, Zimmermann R (2005) Lipolysis: pathway under construction. Curr Opin Lipidol 16:333–340. https://doi.org/10.1097/01.mol.0000169354.20395.1c

    Article  CAS  PubMed  Google Scholar 

  18. Finn PF, Dice JF (2006) Proteolytic and lipolytic responses to starvation. Nutrition 22:830–844. https://doi.org/10.1016/j.nut.2006.04.008

    Article  CAS  PubMed  Google Scholar 

  19. Cui W, Sathyanarayan A, Lopresti M, Aghajan M, Chen C, Mashek DG (2021) Lipophagy-derived fatty acids undergo extracellular efflux via lysosomal exocytosis. Autophagy 17:690–705. https://doi.org/10.1080/15548627.2020.1728097

    Article  CAS  PubMed  Google Scholar 

  20. Yang Z, Klionsky DJ (2010) Mammalian autophagy: core molecular machinery and signaling regulation. Curr Opin Cell Biol 22:124–131. https://doi.org/10.1016/j.ceb.2009.11.014

    Article  CAS  PubMed  Google Scholar 

  21. Wang Y, Chen C, Chen J, Sang T, Peng H, Lin X, Zhao Q, Chen S, Eling T, Wang X (2022) Overexpression of NAG-1/GDF15 prevents hepatic steatosis through inhibiting oxidative stress-mediated dsDNA release and AIM2 inflammasome activation. Redox Biol 52:102322. https://doi.org/10.1016/j.redox.2022.102322

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Wang S, Kuang X, Fang Z, Huang Z, Shi P (2014) Effect of oleic acid on the levels of eight metal ions in human hepatoma SMMC-7721 cells. Biol Trace Elem Res 159:445–450. https://doi.org/10.1007/s12011-014-0018-4

    Article  CAS  PubMed  Google Scholar 

  23. Kurstjens S, van Diepen JA, Overmars-Bos C, Alkema W, Bindels RJM, Ashcroft FM, Tack CJJ, Hoenderop JGJ, de Baaij JHF (2018) Magnesium deficiency prevents high-fat-diet-induced obesity in mice. Diabetologia 61:2030–2042. https://doi.org/10.1007/s00125-018-4680-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Dai B, Li X, Xu J, Zhu Y, Huang L, Tong W, Yao H, Chow DH, Qin L (2021) Synergistic effects of magnesium ions and simvastatin on attenuation of high-fat diet-induced bone loss. Bioact Mater 6:2511–2522. https://doi.org/10.1016/j.bioactmat.2021.01.027

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Su M, Cao D, WangZ, DuanY, HuangY (2021) Fatty acid synthase inhibitor platensimycin intervenes the development of nonalcoholic fatty liver disease in a mouse model. Biomedicines 10(1):5. https://doi.org/10.3390/biomedicines10010005

  26. Han J, Li E, Chen L, Zhang Y, Wei F, Liu J, Deng H, Wang Y (2015) The CREB coactivator CRTC2 controls hepatic lipid metabolism by regulating SREBP1. Nature 524:243–246. https://doi.org/10.1038/nature14557

    Article  CAS  PubMed  Google Scholar 

  27. Ding L, Sun W, Balaz M, He A, Klug M, Wieland S, Caiazzo R, Raverdy V, Pattou F, Lefebvre P, Lodhi IJ, Staels B, Heim M, Wolfrum C (2021) Peroxisomal beta-oxidation acts as a sensor for intracellular fatty acids and regulates lipolysis. Nat Metab 3:1648–1661. https://doi.org/10.1038/s42255-021-00489-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Li J, Li L, Guo D, Li S, Zeng Y, Liu C, Fu R, Huang M, Xie W (2020) Triglyceride metabolism and angiopoietin-like proteins in lipoprotein lipase regulation. Clin Chim Acta 503:19–34. https://doi.org/10.1016/j.cca.2019.12.029

    Article  CAS  PubMed  Google Scholar 

  29. Singh R, Kaushik S, Wang Y, Xiang Y, Novak I, Komatsu M, Tanaka K, Cuervo AM, Czaja MJ (2009) Autophagy regulates lipid metabolism. Nature 458:1131–1135. https://doi.org/10.1038/nature07976

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Codogno P, Mehrpour M, Proikas-Cezanne T (2011) Canonical and non-canonical autophagy: variations on a common theme of self-eating? Nat Rev Mol Cell Biol 13:7–12. https://doi.org/10.1038/nrm3249

    Article  CAS  PubMed  Google Scholar 

  31. Laplante M, Sabatini DM (2012) mTOR signaling in growth control and disease. Cell 149:274–293. https://doi.org/10.1016/j.cell.2012.03.017

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Lee WJ, Kim M, Park HS, Kim HS, Jeon MJ, Oh KS, Koh EH, Won JC, Kim MS, Oh GT, Yoon M, Lee KU, Park JY (2006) AMPK activation increases fatty acid oxidation in skeletal muscle by activating PPARalpha and PGC-1. Biochem Biophys Res Commun 340:291–295. https://doi.org/10.1016/j.bbrc.2005.12.011

    Article  CAS  PubMed  Google Scholar 

  33. Sun L, Zhang S, Yu C, Pan Z, Liu Y, Zhao J, Wang X, Yun F, Zhao H, Yan S, Yuan Y, Wang D, Ding X, Liu G, Li W, Zhao X, Liu Z, Li Y (2015) Hydrogen sulfide reduces serum triglyceride by activating liver autophagy via the AMPK-mTOR pathway. Am J Physiol Endocrinol Metab 309:E925-935. https://doi.org/10.1152/ajpendo.00294.2015

    Article  CAS  PubMed  Google Scholar 

  34. Feeney KA, Hansen LL, Putker MC (2016) Olivares-Yanez, J. Day, L.J. Eades, L.F. Larrondo, N.P. Hoyle, J.S. O’Neill, G. van Ooijen. Daily magnesium fluxes regulate cellular timekeeping and energy balance, Nature 532:375–379. https://doi.org/10.1038/nature17407

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

This study was supported by the National Natural Science Foundation of China (NSFC) (No. 81700716), the Medical Science and Technology Research Foundation of Guangdong Province (No. A2022347), Science and Technology Planning Project in the field of social development of Zhuhai of Guangdong Province (No. 2220004000269), and the Nature Science Foundation of Guangdong Province. (No. 2022A1515011244).

Author information

Author notes

  1. Shiyan Chen and Shunkui Luo contributed equally to the article.

Authors and Affiliations

  1. Department of Endocrinology and Metabolic Diseases, The Fifth Affiliated Hospital of Sun Yat-Sen University, Zhuhai, Guangdong, China

    Shiyan Chen, Shunkui Luo, Jianhui Xie & Yingjuan Zeng

  2. Department of Hepatobiliary Surgery, The Fifth Affiliated Hospital of Sun Yat-Sen University, Zhuhai, Guangdong, China

    Baojia Zou & Jian Li

Authors
  1. Shiyan Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shunkui Luo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Baojia Zou
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jianhui Xie
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jian Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yingjuan Zeng
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors contributed to the study conception and design. The idea design and coordination of the research were jointly completed by Yingjuan Zeng and Jian Li. Material preparation, data collection, and analysis were performed by Shiyan Chen, Shunkui Lou, Jianhui Xie, and Baojia Zou. The first draft of the manuscript was written by Shiyan Chen and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Jian Li or Yingjuan Zeng.

Ethics declarations

Competing Interests

The authors declare no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Chen, S., Luo, S., Zou, B. et al. Magnesium Supplementation Stimulates Autophagy to Reduce Lipid Accumulation in Hepatocytes via the AMPK/mTOR Pathway. Biol Trace Elem Res 201, 3311–3322 (2023). https://doi.org/10.1007/s12011-022-03438-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12011-022-03438-6

Keywords

Search

Navigation