Skip to main content

Advertisement

Log in

Metabolic dysfunction-associated steatotic liver disease and atherosclerosis

  • REVIEW
  • Published:
Current Diabetes Reports Aims and scope Submit manuscript

Abstract

Purpose of review

To update information about the relationship between metabolic dysfunction-associated steatotic liver disease (MASLD) and atherosclerosis. This review emphasizes the potential mechanisms linking MASLD with atherosclerosis and the possible causal relationships between these conditions.

Recent findings

An increased risk of cardiovascular disease is related to MASLD. Several molecular, cellular, and metabolic mechanisms have been described to explain the development of atherothrombosis in MASLD patients. These include atherogenic dyslipidemia, low-grade vascular inflammation, endothelial dysfunction, foam cell formation, proliferation of vascular smooth muscle cells, insulin resistance, gut microbiota dysbiosis, activation of renin-angiotensin and sympathetic nervous systems, hypercoagulability, and decreased fibrinolysis. Also, there is recent evidence suggesting an association between genetically driven liver fat and coronary heart disease mediated by the causal effect of apoB-containing lipoproteins. Several meta-analyses and systematic reviews have reported a strong association between MASLD and cardiovascular outcomes.

Summary

MASLD is an important and independent risk factor for atherosclerosis development. Multiple mechanisms may be involved in this association. Further research is required to establish a causal association between MASLD and atherosclerosis.

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

Access this article

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

Instant access to the full article PDF.

Fig. 1

Similar content being viewed by others

Data Availability

No datasets were generated or analysed during the current study.

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Bril F, Cusi K. Nonalcoholic fatty liver disease: The new complication of type 2 diabetes mellitus. Endocrinol Metab Clin N Am. 2016;45:765–81.

    Article  Google Scholar 

  2. Bril F, Cusi K. Management of nonalcoholic fatty liver disease in patients with type 2 diabetes: A call to action. Diabetes Care. 2017;40:419–30.

    Article  PubMed  Google Scholar 

  3. Eslam M, Newsome PN, Sarin SK, Anstee QM, Targher G, Romero-Gomez M, et al. A new definition for metabolic dysfunction-associated fatty liver disease: An international expert consensus statement. J Hepatol. 2020;73:202–9.

    Article  PubMed  Google Scholar 

  4. Rinella ME, Lazarus JV, Ratziu V, Francque SM, Sanyal AJ, et al. A multi-society Delphi consensus statement on new fatty liver disease nomenclature. J Hepatol. 2023;79:1542–56.

    Article  CAS  PubMed  Google Scholar 

  5. Zheng KI, Sun DQ, Jin Y, Zhu PW, Zheng MH. Clinical utility of the MAFLD definition. J Hepatol. 2021;74:989–91.

    Article  PubMed  Google Scholar 

  6. Hagström H, Vessby J, Ekstedt M, Shang Y. 99% of patients with NAFLD meet MASLD criteria and natural history is therefore identical. J Hepatol. 2024;80(2):e76–7.

    Article  PubMed  Google Scholar 

  7. Chalasani N, Younossi Z, Lavine JE, Diehl AM, Brunt EM, Cusi K, Charlton M, Sanyal AJ. The diagnosis and management of non-alcoholic fatty liver disease: practice guideline by the American Gastroenterological Association, American Association for the Study of Liver Diseases, and American College of Gastroenterology. Gastroenterology. 2012;142:1592–609.

    Article  PubMed  Google Scholar 

  8. Balta S. Atherosclerosis and non-alcoholic fatty liver disease. Angiology. 2022;73:701–11.

    Article  CAS  PubMed  Google Scholar 

  9. Niederseer D, Wernly B, Aigner E, Stickel F, Datz C. NAFLD and Cardiovascular Diseases: Epidemiological, Mechanistic and Therapeutic Considerations. J Clin Med. 2021;10(3):467.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Brea A, Puzo J. Non-alcoholic fatty liver disease and cardiovascular risk. Int J Cardiol. 2013;167:1109–17.

    Article  PubMed  Google Scholar 

  11. Leey J, Cusi K. Editorial: diabetes, obesity and clinical inertia-the recipe for advanced NASH. Aliment Pharmacol Ther. 2018;47:1220–1.

    Article  CAS  PubMed  Google Scholar 

  12. Davis TME. Diabetes and metabolic dysfunction-associated fatty liver disease. Metabolism. 2021;123: 154868.

    Article  CAS  PubMed  Google Scholar 

  13. Wen W, Li H, Wang C, Chen C, Tang J, Zhou M, Hong X, Cheng Y, Wu Q, Zhang X, Feng Z, Wang M. Metabolic dysfunction-associated fatty liver disease and cardiovascular disease: a meta-analysis. Front Endocrinol (Lausanne). 2022;13: 934225.

    Article  PubMed  Google Scholar 

  14. Mantovani A, Csermely A, Tilg H, Byrne CD, Targher G. Comparative effects of non-alcoholic fatty liver disease and metabolic dysfunction-associated fatty liver disease on risk of incidente cardiovascular events: a meta-analysis of about 13 million individuals. Gut. 2023;72:1433–6.

    Article  PubMed  Google Scholar 

  15. Schonmann Y, Yeshua H, Bentov I, Zelber-Sagi S. Liver fbrosis marker is an independent predictor of cardiovascular morbidity and mortality in the general population. Dig Liver Dis. 2021;53:79–85.

    Article  CAS  PubMed  Google Scholar 

  16. Baratta F, Pastori D, Angelico F, Balla A, Paganini AM, Cocomello N, Ferro D, Violi F, Sanyal AJ, Del Ben M. Nonalcoholic fatty liver disease and fibrosis associated with increased risk of cardiovascular events in a prospective study. Clin Gastroenterol Hepatol. 2020;18:2324-2331.e4.

    Article  PubMed  Google Scholar 

  17. Tamaki N, Kurosaki M, Takahashi Y, Itakura Y, Inada K, Kirino S, Yamashita K, Sekiguchi S, Hayakawa Y, Osawa L, Higuchi M, Takaura K, Maeyashiki C, Kaneko S, Yasui Y, Tsuchiya K, Nakanishi H, Itakura J, Izumi N. Liver fbrosis and fatty liver as independent risk factors for cardiovascular disease. J Gastroenterol Hepatol. 2021;36:2960–6.

    Article  CAS  PubMed  Google Scholar 

  18. Han E, Lee YH, Lee JS, Lee HW, Kim BK, Park JY, Kim DY, Ahn SH, Lee BW, Kang ES, Cha BS, Kim SU. Fibrotic burden determines cardiovascular risk among subjects with metabolic dysfunction-associated fatty liver disease. Gut Liver. 2022;16:786–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Duell PB, Welty FK, Miller M, Chait A, Hammond G, Ahmad Z, et al. Nonalcoholic fatty liver disease and cardiovascular risk: a scientific statement from the American Heart Association. Arterioscler Thromb Vasc Biol. 2022;42:e168–85.

    Article  CAS  PubMed  Google Scholar 

  20. Kasper P, Martin A, Lang S, Kütting F, Goeser T, Demir M, Steffen HM. NAFLD and cardiovascular diseases: a clinical review. Clin Res Cardiol. 2021;110:921–93721.

    Article  PubMed  Google Scholar 

  21. •Zhang L, She ZG, Li H, Zhang XJ. Non-alcoholic fatty liver disease: a metabolic burden promoting atherosclerosis. Clin Sci (Lond). 2020;134:1775–99. This review summarizes the key molecular events and cellular factors contributing to the metabolic burden induced by NAFLD on atherosclerosis.

    Article  CAS  PubMed  Google Scholar 

  22. •Li M, Wang H, Zhang XJ, Cai J, Li H. NAFLD: an emerging causal factor for cardiovascular disease. Physiology (Bethesda). 2023;38(6):0. This review summarizes the evidence from prospective clinical and Mendelian randomization studies that underscore the potential causal relationship between NAFLD and cardiovascular disease.

  23. Bali AD, Rosenzveig A, Frishman WH, Aronow WS. Nonalcoholic fatty liver disease and cardiovascular disease: causation or association. Cardiol Rev. 2023;24:e000537.

  24. Bril F, Lomonaco R, Cusi K. The challenge of managing dyslipidemia in patients with nonalcoholic fatty liver disease. Clin Lipidol. 2012;7:471–81.

    Article  CAS  Google Scholar 

  25. Martin A, Lang S, Goeser T, Demir M, Steffen HM, Kasper P. Management of dyslipidemia in patients with non-alcoholic fatty liver disease. Curr Atheroscler Rep. 2022;24:533–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Behbodikhah J, Ahmed S, Elsayi A, Kasselman LJ, De Leon J, Glass AD, Reiss AB. Apolipoprotein B and cardiovascular disease: biomarker and potential therapeutic target. Metabolites. 2021;11:690.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Cole J, Zubirán R, Wolska A, Jialal I, Remaley AT. Use of apolipoprotein B in the era of precision medicine: time for a paradigm change? J Clin Med. 2023;12:5737.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Matikainen N, Taskinen MR, Stennabb S, Lundbom N, Hakkarainen A, Vaaralahti K, Raivio T. Decrease in circulating fibroblast growth factor 21 after an oral fat load is related to postprandial triglyceride-rich lipoproteins and liver fat. Eur J Endocrinol. 2012;166:487–92.

    Article  CAS  PubMed  Google Scholar 

  29. Mehta A, Shapiro MD. Apolipoproteins in vascular biology and atherosclerotic disease. Nat Rev Cardiol. 2022;19:168–79.

    Article  CAS  PubMed  Google Scholar 

  30. Hegele RA. Apolipoprotein C-III inhibition to lower triglycerides: one ring to rule them all? Eur Heart J. 2022;43:1413–5.

    Article  PubMed  Google Scholar 

  31. de la Parra Soto LG, Gutiérrez-Uribe JA, Sharma A, Ramírez-Jiménez AK. Is apo-CIII the new cardiovascular target? An analysis of its current clinical and dietetic therapies. Nutr Metab Cardiovasc Dis. 2022;32:295–308.

    Article  PubMed  Google Scholar 

  32. Deprince A, Hennuyer N, Kooijman S, Pronk ACM, Baugé E, Lienard V, et al. Apolipoprotein F is reduced in humans with steatosis and controls plasma triglyceride-rich lipoprotein metabolism. Hepatology. 2023;77:1287–302.

    Article  PubMed  Google Scholar 

  33. Hafiane A, Gianopoulos I, Sorci-Thomas MG, Daskalopoulou SS. Current models of apolipoproteina A-I lipidation by adenosine triphosphate binding cassette transporter A1. Curr Opin Lipidol. 2022;33:139–45.

    Article  CAS  PubMed  Google Scholar 

  34. Naito C, Hashimoto M, Watanabe K, Shirai R, Takahashi Y, Kojima M, Watanabe R, Sato K, Iso Y, Matsuyama TA, Suzuki H, Ishibashi-Ueda H, Watanabe T. Facilitatory effects of fetuin-A on atherosclerosis. Atherosclerosis. 2016;246:344–51.

    Article  CAS  PubMed  Google Scholar 

  35. Gupta RM, Libby P, Barton M. Linking regulation of nitric oxide to endothelin-1: the yin and yang of vascular tone in the atherosclerotic plaque. Atherosclerosis. 2020;292:201–3.

    Article  CAS  PubMed  Google Scholar 

  36. Rafnsson A, Matic LP, Lengquist M, Mahdi A, Shemyakin A, Paulsson-Berne G, Hansson GK, Gabrielsen A, Hedin U, Yang J, Pernow J. Endothelin-1 increases expression and activity of arginase 2 via ETB receptors and is co-expressed with arginase 2 in human atherosclerotic plaques. Atherosclerosis. 2020;292:215–23.

    Article  CAS  PubMed  Google Scholar 

  37. Loffredo L, Baratta F, Ludovica P, Battaglia S, Carnevale R, Nocella C, Novo M, Pannitteri G, Ceci F, Angelico F, Violi F, Del Ben M. Effects of dark chocolate on endothelial function in patients with non-alcoholic steatohepatitis. Nutr Metab Cardiovasc Dis. 2018;28:143–9.

    Article  CAS  Google Scholar 

  38. Jiang M, Zhao XM, Jiang ZS, Wang GX, Zhang DW. Protein tyrosine nitration in atherosclerotic endothelial dysfunction. Clin Chim Acta. 2022;529:34–41.

    Article  CAS  PubMed  Google Scholar 

  39. Love KM, Barrett EJ, Malin SK, Reusch JEB, Rogensteiner JG, Liu Z. Diabetes pathogenesis and management: the endothelium comes of age. J Mol Cell Biol. 2021;13:500–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Su X, Chen S, Liu J, Feng Y, Han E, Hao X, Liao M, Cai J, Zhang S, Niu J, He S, Huang S, Lo K, Zeng F. Composition of gut microbiota and non-alcoholic fatty liver disease: a systematic review and meta-analysis. Obes Rev. 2023;9: e13646.

    Google Scholar 

  41. Jadhav PA, Thomas AB, Nanda RK, Chitlange SS. Unveiling the role of gut dysbiosis in non-alcoholic fatty liver disease. Eur J Gastroenterol Hepatol. 2023;35(12):1324–33.

  42. AL Samarraie A, Pichette M, Rousseau G. Role of the gut microbiome in the development of atherosclerotic cardiovascular disease. Int J Mol Sci. 2023;24:5420.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Oktaviono YH, Dyah Lamara A, Saputra PBT, Arnindita JN, Pasahari D, Saputra ME, Suasti NMA. The roles of trimethylamine-N-oxide in atherosclerosis and its potential therapeutic aspect: a literature review. Biomol Biomed. 2023;23(6):936–48.

  44. Jing L, Zhang H, Xiang Q, Shen L, Guo X, Zhai C, Hu H. Targeting trimethylamine N-oxide: a new therapeutic strategy for alleviating atherosclerosis. Front Cardiovasc Med. 2022;9: 864600.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Querio G, Antoniotti S, Geddo F, Levi R, Gallo MP. Modulation of endothelial function by TMAO, a gut microbiota-derived metabolite. Int J Mol Sci. 2023;24:5806.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Bataller R, Sancho-Bru P, Ginès P, Lora JM, Al-Garawi A, Solé M, Colmenero J, Nicolás JM, Jiménez W, Weich N, Gutiérrez-Ramos JC, Arroyo V, Rodés J. Activated human hepatic stellate cells express the renin-angiotensin system and synthesize angiotensin II. Gastroenterology. 2003;125:117–25.

    Article  CAS  PubMed  Google Scholar 

  47. Aminuddin A, Cheong SS, Roos NAC, Ugusman A. Smoking and unstable plaque in acute coronary syndrome: a systematic review of the role of matrix metalloproteinases. Int J Med Sci. 2023;20:482–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Mantovani A, Csermely A, Petracca G, Beatrice G, Corey KE, Simon TG, Byrne CD, Targher G. Non-alcoholic fatty liver disease and risk of fatal and non-fatal cardiovascular events: an updated systematic review and meta-analysis. Lancet Gastroenterol Hepatol. 2021;6:903–13.

    Article  PubMed  Google Scholar 

  49. Koulaouzidis G, Charisopoulou D, Kukla M, Marlicz W, Rydzewska G, Koulaouzidis A, Skonieczna-Zydecka K. Association of non-alcoholic fatty liver disease with coronary artery calcification progression: a systematic review and meta-analysis. Prz Gastroenterology. 2021;16:196–206.

    CAS  Google Scholar 

  50. Alon L, Corica B, Raparelli V, Cangemi R, Basili S, Proietti M, Romiti GF. Risk of cardiovascular events in patients with non-alcoholic fatty liver disease: a systematic review and meta-analysis. Eur J Prev Cardiol. 2022;29:938–46.

    Article  PubMed  Google Scholar 

  51. Lee H, Lee YH, Kim SU, Kim HC. Metabolic dysfunction-associated fatty liver disease and incident cardiovascular risk: a nationwide cohort study. Clin Gastroenterol Hepatol. 2021;19:2138–47.

    Article  PubMed  Google Scholar 

  52. Quek J, Ng CH, Tang ASP, Chew N, Chan M, Khoo CM, et al. Metabolic associated fatty liver disease increases the risk of systemic complications and mortality. A meta-analysis and systematic review of 12,620,736 individuals. Endocr Pract. 2022;28:667–72.

    Article  PubMed  Google Scholar 

  53. Fu CE, Ng CH, Yong JN, Chan KE, Xiao J, et al. A meta-analysis on associated risk of mortality in nonalcoholic fatty liver disease. Endocr Pract. 2023;29:33–9.

    Article  PubMed  Google Scholar 

  54. Bisaccia G, Ricci F, Khanji MY, Sorella A, Melchiorre E, et al. Cardiovascular morbidity and mortality related to non-alcoholic fatty liver disease: A systematic review and meta-analysis. Curr Probl Cardiol. 2023;48: 101643.

    Article  PubMed  Google Scholar 

  55. Jamalinia M, Zare F, Lankarani KB. Systematic review and meta-analysis: Association between liver fibrosis and subclinical atherosclerosis in nonalcoholic fatty liver disease. Aliment Pharmacol Ther. 2023;58:384–94.

    Article  CAS  PubMed  Google Scholar 

  56. Lauridsen BK, Stender S, Kristensen TS, Kofoed KF, Køber L, Nordestgaard BG, Tybjaerg-Hansen A. Liver fat content, non-alcoholic fatty liver disease, and ischaemic heart disease: Mendelian randomization and meta-analysis of 279,013 individuals. Eur Heart J. 2018;39:385–93.

    Article  CAS  PubMed  Google Scholar 

  57. Brouwers MCGJ, Simons N, Stehouwer CDA, Koek GH, Schaper NC, Isascs A. Relationship between nonalcoholic fatty liver disease susceptibility genes and coronary artery disease. Hepatol Commun. 2019;3:587–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Castillo-Núnez Y, Morales-Villegas E, Aguilar-Salinas CA. Triglyceride-rich lipoproteins: Their role in atherosclerosis. Rev Invest Clin. 2022;74:061–70.

    PubMed  Google Scholar 

  59. Björnson E, Samaras D, Adiels M, Kullberg J, Bäckhed F, Bergström G, Gummesson A. Mediating role of atherogenic lipoproteins in the relationship between liver fat and coronary artery calcification. Sci Rep. 2023;13:13217.

    Article  PubMed  PubMed Central  Google Scholar 

  60. ••Björnson E, Adiels M, Bergström G, Gummesson A. The relationship between genetic liver fat and coronary heart disease is explained by apoB-containing lipoproteins. Atherosclerosis. 2024;388:117397. https://doi.org/10.1016/j.atherosclerosis.2023.117397this is a genome-wide association study in the UK Biobank, using MR analyses, suggesting that the relationship between genetically-determinated liver fat and coronary heart disease is mediated by the causal effect of apoB.

  61. Ren Z, Simons PIHG, Wesselius A, Stehouwer CDA, Brouwers MCGJ. Relationship between NAFLD and coronary artery disease: A Mendelian randomization study. Hepatology. 2023;77:230–8.

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Contributions

All the authors wrote and reviewed the manuscript's text (YC, GG, PA, RA). YC prepared Fig. 1.

Corresponding author

Correspondence to Yulino Castillo-Núñez.

Ethics declarations

Conflict of Interest

The authors declare no competing of interests.

Human and Animal Rights and Informed of Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

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 (e.g. a society or other partner) 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

Castillo-Núñez, Y., Almeda-Valdes, P., González-Gálvez, G. et al. Metabolic dysfunction-associated steatotic liver disease and atherosclerosis. Curr Diab Rep (2024). https://doi.org/10.1007/s11892-024-01542-6

Download citation

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s11892-024-01542-6

Keywords

Navigation