Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Mini Review
  • Published:

Role of high-salt diet in non-alcoholic fatty liver disease: a mini-review of the evidence

European Journal of Clinical Nutrition volume 76, pages 1053–1059 (2022)Cite this article

Subjects

Abstract

With the rising incidence of both obesity and diabetes, non-alcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease worldwide. However, lifestyle intervention remains to be an effective approach for NAFLD due to lack of therapeutic medication. Recently, salt, an essential micronutrient free of calories, has raised a global concern owing to its wide-range healthy relevance. Accumulated evidence has suggested that a long-term high-salt diet (HSD) independently increases the risk of NAFLD. In the past decades, a number of studies have been reported regarding the mechanism of much investigation concerning HSD-induced NAFLD. Here, we review the updates in epidemiology and molecular mechanism of HSD-induced NAFLD and provide a novel insight into the role of HSD in the regulation of lipid metabolism.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1
Fig. 2: Potential impaired insulin signalling steps in high-salt induced NAFLD.

Similar content being viewed by others

References

  1. Younossi Z, Tacke F, Arrese M, Chander Sharma B, Mostafa I, Bugianesi E, et al. Global Perspectives on Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis. Hepatology. 2019;69:2672–82.

    Article  PubMed  Google Scholar 

  2. Li J, Zou B, Yeo YH, Feng Y, Xie X, Lee DH, et al. Prevalence, incidence, and outcome of non-alcoholic fatty liver disease in Asia, 1999-2019: a systematic review and meta-analysis. Lancet Gastroenterol Hepatol. 2019;4:389–98.

    Article  PubMed  Google Scholar 

  3. Lonardo A, Nascimbeni F, Mantovani A, Targher G. Hypertension, diabetes, atherosclerosis and NASH: Cause or consequence? J Hepatol. 2018;68:335–52.

    Article  PubMed  Google Scholar 

  4. Stefan N, Häring HU, Cusi K. Non-alcoholic fatty liver disease: causes, diagnosis, cardiometabolic consequences, and treatment strategies. Lancet Diabetes Endocrinol. 2019;7:313–24.

    Article  PubMed  Google Scholar 

  5. Guideline: Sodium Intake for Adults and Children. Geneva: World Health Organization; 2012.

  6. Stamler J, Chan Q, Daviglus ML, Dyer AR, Van Horn L, Garside DB, et al. Relation of Dietary Sodium (Salt) to Blood Pressure and Its Possible Modulation by Other Dietary Factors: The INTERMAP Study. Hypertension. 2018;71:631–37.

    Article  CAS  PubMed  Google Scholar 

  7. Zhang Y, Li F, Liu FQ, Chu C, Wang Y, Wang D, et al. Elevation of Fasting Ghrelin in Healthy Human Subjects Consuming a High-Salt Diet: A Novel Mechanism of Obesity? Nutrients. 2016;8:323.

    Article  PubMed Central  CAS  Google Scholar 

  8. Lanaspa MA, Kuwabara M, Andres-Hernando A, Li N, Cicerchi C, Jensen T, et al. High salt intake causes leptin resistance and obesity in mice by stimulating endogenous fructose production and metabolism. Proc Natl Acad Sci USA. 2018;115:3138–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Ogihara T, Asano T, Ando K, Chiba Y, Sekine N, Sakoda H, et al. Insulin resistance with enhanced insulin signaling in high-salt diet-fed rats. Diabetes. 2001;50:573–83.

    Article  CAS  PubMed  Google Scholar 

  10. Horikawa C, Yoshimura Y, Kamada C, Tanaka S, Tanaka S, Hanyu O, et al. Dietary sodium intake and incidence of diabetes complications in Japanese patients with type 2 diabetes: analysis of the Japan Diabetes Complications Study (JDCS). J Clin Endocrinol Metab. 2014;99:3635–43.

    Article  CAS  PubMed  Google Scholar 

  11. Abdulai T, Runqi T, Mao Z, Oppong TB, Amponsem-Boateng C, Wang Y, et al. Preference for High Dietary Salt Intake Is Associated with Undiagnosed Type 2 Diabetes: the Henan Rural Cohort. Front Nutr. 2020;7:537049.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. Ge Z, Guo X, Chen X, Tang J, Yan L, Ren J, et al. Association between 24 h urinary sodium and potassium excretion and the metabolic syndrome in Chinese adults: the Shandong and Ministry of Health Action on Salt and Hypertension (SMASH) study. Br J Nutr. 2015;113:996–1002.

    Article  CAS  PubMed  Google Scholar 

  13. Yoshida Y, Kosaki K, Sugasawa T, Matsui M, Yoshioka M, Aoki K, et al. High Salt Diet Impacts the Risk of Sarcopenia Associated with Reduction of Skeletal Muscle Performance in the Japanese Population. Nutrients. 2020;12:3474.

    Article  CAS  PubMed Central  Google Scholar 

  14. Zhou L, Yang Y, Feng Y, Zhao X, Fan Y, Rong J, et al. Association between dietary sodium intake and non-alcoholic fatty liver disease in the US population. Public Health Nutr. 2021;24:993–1000.

    Article  PubMed  Google Scholar 

  15. Huh JH, Lee KJ, Lim JS, Lee MY, Park HJ, Kim MY, et al. High Dietary Sodium Intake Assessed by Estimated 24-h Urinary Sodium Excretion Is Associated with NAFLD and Hepatic Fibrosis. PLoS ONE 2015;10:e0143222.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Choi Y, Lee JE, Chang Y, Kim MK, Sung E, Shin H, et al. Dietary sodium and potassium intake in relation to non-alcoholic fatty liver disease. Br J Nutr. 2016;116:1447–56.

    Article  CAS  PubMed  Google Scholar 

  17. Shen X, Jin C, Wu Y, Zhang Y, Wang X, Huang W, et al. Prospective study of perceived dietary salt intake and the risk of non-alcoholic fatty liver disease. J Hum Nutr Diet. 2019;32:802–09.

    Article  CAS  PubMed  Google Scholar 

  18. van den Berg EH, Gruppen EG, Blokzijl H, Bakker SJL, Dullaart RPF. Higher Sodium Intake Assessed by 24 h Urinary Sodium Excretion Is Associated with Non-Alcoholic Fatty Liver Disease: The PREVEND Cohort Study. J Clin Med. 2019;8:2157.

    Article  PubMed Central  CAS  Google Scholar 

  19. McLean RM, Williams SM, Te Morenga LA, Mann JI. Spot urine and 24-h diet recall estimates of dietary sodium intake from the 2008/09 New Zealand Adult Nutrition Survey: a comparison. Eur J Clin Nutr. 2018;72:1120–27.

    Article  PubMed  Google Scholar 

  20. He FJ, Marrero NM, MacGregor GA. Salt intake is related to soft drink consumption in children and adolescents: a link to obesity? Hypertension. 2008;51:629–34.

    Article  CAS  PubMed  Google Scholar 

  21. Bolhuis DP, Costanzo A, Newman LP, Keast RS. Salt Promotes Passive Overconsumption of Dietary Fat in Humans. J Nutr. 2016;146:838–45.

    Article  CAS  PubMed  Google Scholar 

  22. Ruepp B, Bohren KM, Gabbay KH. Characterization of the osmotic response element of the human aldose reductase gene promoter. Proc Natl Acad Sci USA. 1996;93:8624–29.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Kanbay M, Guler B, Ertuglu LA, Dagel T, Afsar B, Incir S, et al. The Speed of Ingestion of a Sugary Beverage Has an Effect on the Acute Metabolic Response to Fructose. Nutrients. 2021;13:1916.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Stookey JD, Barclay D, Arieff A, Popkin BM. The altered fluid distribution in obesity may reflect plasma hypertonicity. Eur J Clin Nutr. 2007;61:190–99.

    Article  CAS  PubMed  Google Scholar 

  25. Stookey JD, Constant F, Popkin BM, Gardner CD. Drinking water is associated with weight loss in overweight dieting women independent of diet and activity. Obes (Silver Spring). 2008;16:2481–88.

    Article  Google Scholar 

  26. Kanbay M, Aslan G, Afsar B, Dagel T, Siriopol D, Kuwabara M, et al. Acute effects of salt on blood pressure are mediated by serum osmolality. J Clin Hypertens (Greenwich). 2018;20:1447–54.

    Article  CAS  Google Scholar 

  27. Enhörning S, Malan L. Copeptin relates to a fatty liver and measures of obesity in a South African population with mixed ethnicities. Endocrine. 2019;65:304–11.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Barchetta I, Enhörning S, Cimini FA, Capoccia D, Chiappetta C, Di Cristofano C, et al. Elevated plasma copeptin levels identify the presence and severity of non-alcoholic fatty liver disease in obesity. BMC Med. 2019;17:85.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Enhörning S, Melander O. The Vasopressin System in the Risk of Diabetes and Cardiorenal Disease, and Hydration as a Potential Lifestyle Intervention. Ann Nutr Metab. 2018;72:21–27.

    Article  PubMed  CAS  Google Scholar 

  30. Enhörning S, Bankir L, Bouby N, Struck J, Hedblad B, Persson M, et al. Copeptin, a marker of vasopressin, in abdominal obesity, diabetes and microalbuminuria: the prospective Malmö Diet and Cancer Study cardiovascular cohort. Int J Obes (Lond). 2013;37:598–603.

    Article  CAS  Google Scholar 

  31. Andres-Hernando A, Jensen TJ, Kuwabara M, Orlicky DJ, Cicerchi C, Li N, et al. Vasopressin mediates fructose-induced metabolic syndrome by activating the V1b receptor. JCI Insight. 2021;6:e140848.

    Article  PubMed Central  Google Scholar 

  32. DeFronzo RA, Ferrannini E. Insulin resistance. A multifaceted syndrome responsible for NIDDM, obesity, hypertension, dyslipidemia, and atherosclerotic cardiovascular disease. Diabetes Care. 1991;14:173–94.

    Article  CAS  PubMed  Google Scholar 

  33. Khan RS, Bril F, Cusi K, Newsome PN. Modulation of Insulin Resistance in Nonalcoholic Fatty Liver Disease. Hepatology. 2019;70:711–24.

    CAS  PubMed  Google Scholar 

  34. Ames RP. The effect of sodium supplementation on glucose tolerance and insulin concentrations in patients with hypertension and diabetes mellitus. Am J Hypertens. 2001;14:653–59.

    Article  CAS  PubMed  Google Scholar 

  35. Wan Z, Wen W, Ren K, Zhou D, Liu J, Wu Y, et al. Involvement of NLRP3 inflammasome in the impacts of sodium and potassium on insulin resistance in normotensive Asians. Br J Nutr. 2018;119:228–37.

    Article  CAS  PubMed  Google Scholar 

  36. Meland E, Laerum E, Aakvaag A, Ulvik RJ, Høstmark AT. Salt restriction: effects on lipids and insulin production in hypertensive patients. Scand J Clin Lab Investig. 1997;57:501–05.

    Article  CAS  Google Scholar 

  37. Foo M, Denver AE, Coppack SW, Yudkin JS. Effect of salt-loading on blood pressure, insulin sensitivity and limb blood flow in normal subjects. Clin Sci (Lond). 1998;95:157–64.

    Article  CAS  Google Scholar 

  38. Townsend RR, Kapoor S, McFadden CB. Salt intake and insulin sensitivity in healthy human volunteers. Clin Sci (Lond). 2007;113:141–48.

    Article  CAS  Google Scholar 

  39. Anai M, Funaki M, Ogihara T, Terasaki J, Inukai K, Katagiri H, et al. Altered expression levels and impaired steps in the pathway to phosphatidylinositol 3-kinase activation via insulin receptor substrates 1 and 2 in Zucker fatty rats. Diabetes. 1998;47:13–23.

    Article  CAS  PubMed  Google Scholar 

  40. Nagasaki M, Nakai N, Oshida Y, Li Z, Xu M, Obayashi M, et al. Exercise training prevents maturation-induced decreases in insulin receptor substrate-1 and phosphatidylinositol 3-kinase in rat skeletal muscle. Metabolism. 2000;49:954–59.

    Article  CAS  PubMed  Google Scholar 

  41. Ye JM, Doyle PJ, Iglesias MA, Watson DG, Cooney GJ, Kraegen EW. Peroxisome proliferator-activated receptor (PPAR)-alpha activation lowers muscle lipids and improves insulin sensitivity in high fat-fed rats: comparison with PPAR-gamma activation. Diabetes. 2001;50:411–17.

    Article  CAS  PubMed  Google Scholar 

  42. Pickavance LC, Brand CL, Wassermann K, Wilding JP. The dual PPARalpha/gamma agonist, ragaglitazar, improves insulin sensitivity and metabolic profile equally with pioglitazone in diabetic and dietary obese ZDF rats. Br J Pharmacol. 2005;144:308–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Dornas WC, de Lima WG, dos Santos RC, Guerra JF, de Souza MO, Silva M, et al. High dietary salt decreases antioxidant defenses in the liver of fructose-fed insulin-resistant rats. J Nutr Biochem. 2013;24:2016–22.

    Article  CAS  PubMed  Google Scholar 

  44. Donovan DS, Solomon CG, Seely EW, Williams GH, Simonson DC. Effect of sodium intake on insulin sensitivity. Am J Physiol. 1993;264:E730–34.

    CAS  PubMed  Google Scholar 

  45. Sears B, Perry M. The role of fatty acids in insulin resistance. Lipids Health Dis. 2015;14:121.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  46. Fonseca-Alaniz MH, Brito LC, Borges-Silva CN, Takada J, Andreotti S, Lima FB. High dietary sodium intake increases white adipose tissue mass and plasma leptin in rats. Obes (Silver Spring). 2007;15:2200–08.

    Article  CAS  Google Scholar 

  47. Maury E, Brichard SM. Adipokine dysregulation, adipose tissue inflammation and metabolic syndrome. Mol Cell Endocrinol. 2010;314:1–16.

    Article  CAS  PubMed  Google Scholar 

  48. Gabbay KH. Hyperglycemia, polyol metabolism, and complications of diabetes mellitus. Annu Rev Med. 1975;26:521–36.

    Article  CAS  PubMed  Google Scholar 

  49. Yan LJ. Redox imbalance stress in diabetes mellitus: Role of the polyol pathway. Anim Model Exp Med. 2018;1:7–13.

    Article  Google Scholar 

  50. Lanaspa MA, Ishimoto T, Li N, Cicerchi C, Orlicky DJ, Ruzycki P, et al. Endogenous fructose production and metabolism in the liver contributes to the development of metabolic syndrome. Nat Commun. 2013;4:2434.

    Article  PubMed  CAS  Google Scholar 

  51. Liu L, Li T, Liao Y, Wang Y, Gao Y, Hu H, et al. Triose Kinase Controls the Lipogenic Potential of Fructose and Dietary Tolerance. Cell Metab. 2020;32:605–18. e7

    Article  CAS  PubMed  Google Scholar 

  52. Munshi MK, Uddin MN, Glaser SS. The role of the renin-angiotensin system in liver fibrosis. Exp Biol Med (Maywood). 2011;236:557–66.

    Article  CAS  Google Scholar 

  53. Hyndman KA, Mironova EV, Giani JF, et al. Collecting Duct Nitric Oxide Synthase 1ß Activation Maintains Sodium Homeostasis During High Sodium Intake Through Suppression of Aldosterone and Renal Angiotensin II Pathways. J Am Heart Assoc. 2017;6:e006896.

    Article  PubMed  PubMed Central  Google Scholar 

  54. Hirose A, Ono M, Saibara T, Nozaki Y, Masuda K, Yoshioka A, et al. Angiotensin II type 1 receptor blocker inhibits fibrosis in rat nonalcoholic steatohepatitis. Hepatology. 2007;45:1375–81.

    Article  CAS  PubMed  Google Scholar 

  55. Lely AT, Krikken JA, Bakker SJ, Boomsma F, Dullaart RP, Wolffenbuttel BH, et al. Low dietary sodium and exogenous angiotensin II infusion decrease plasma adiponectin concentrations in healthy men. J Clin Endocrinol Metab. 2007;92:1821–26.

    Article  CAS  PubMed  Google Scholar 

  56. Bentley-Lewis R, Adler GK, Perlstein T, Seely EW, Hopkins PN, Williams GH, et al. Body mass index predicts aldosterone production in normotensive adults on a high-salt diet. J Clin Endocrinol Metab. 2007;92:4472–75.

    Article  CAS  PubMed  Google Scholar 

  57. Rajagopalan S, Duquaine D, King S, Pitt B, Patel P. Mineralocorticoid receptor antagonism in experimental atherosclerosis. Circulation. 2002;105:2212–16.

    Article  CAS  PubMed  Google Scholar 

  58. Leopold JA, Dam A, Maron BA, Scribner AW, Liao R, Handy DE, et al. Aldosterone impairs vascular reactivity by decreasing glucose-6-phosphate dehydrogenase activity. Nat Med. 2007;13:189–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Shibata S, Fujita T. Mineralocorticoid receptors in the pathophysiology of chronic kidney diseases and the metabolic syndrome. Mol Cell Endocrinol. 2012;350:273–80.

    Article  CAS  PubMed  Google Scholar 

  60. Pojoga LH, Williams JS, Yao TM, Kumar A, Raffetto JD, do Nascimento GR, et al. Histone demethylase LSD1 deficiency during high-salt diet is associated with enhanced vascular contraction, altered NO-cGMP relaxation pathway, and hypertension. Am J Physiol Heart Circ Physiol. 2011;301:H1862–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Ricchiuti V, Lapointe N, Pojoga L, Yao T, Tran L, Williams GH, et al. Dietary sodium intake regulates angiotensin II type 1, mineralocorticoid receptor, and associated signaling proteins in heart. J Endocrinol. 2011;211:47–54.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We would like to thank acknowledge Zhongshan hospital, Fudan University for assistance with obtaining copies of research and review papers.

Author information

Authors and Affiliations

  1. Department of Endocrinology and Metabolism, Zhongshan hospital, Fudan University, 200032, Shanghai, China

    Jing Xu & Fei Mao

Authors
  1. Jing Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Fei Mao
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Conceptualization: JX and FM; Writing: JX; Supervision and revision: FM.

Corresponding author

Correspondence to Fei Mao.

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

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Xu, J., Mao, F. Role of high-salt diet in non-alcoholic fatty liver disease: a mini-review of the evidence. Eur J Clin Nutr 76, 1053–1059 (2022). https://doi.org/10.1038/s41430-021-01044-8

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41430-021-01044-8

Search

Advanced search

Quick links