Skip to main content

Advertisement

Log in

Protective Roles of Shilajit in Modulating Resistin, Adiponectin, and Cytokines in Rats with Non-alcoholic Fatty Liver Disease

  • Original Article
  • Published:
Chinese Journal of Integrative Medicine Aims and scope Submit manuscript

Abstract

Objective

To evaluate the effect of Shilajit, a medicine of Ayurveda, on the serum changes in cytokines and adipokines caused by non-alcoholic fatty liver disease (NAFLD).

Methods

After establishing fatty liver models by feeding a high-fat diet (HFD) for 12 weeks, 35 Wistar male rats were randomly divided into 5 groups, including control (standard diet), Veh (HFD + vehicle), high-dose Shilajit [H-Sh, HFD + 250 mg/(kg·d) Shilajit], low-dose Shilajit [L-Sh, HFD + 150 mg/(kg·d) Shilajit], and pioglitazone [HFD + 10 mg/(kg·d) pioglitazone] groups, 7 rats in each group. After 2-week of gavage administration, serum levels of glucose, insulin, interleukin 1beta (IL-1β), IL-6, IL-10, tumor necrosis factor-alpha (TNF-α), adiponectin, and resistin were measured, and insulin resistance index (HOMA-IR) was calculated.

Results

After NAFLD induction, the serum level of IL-10 significantly increased and serum IL-1β, TNF-α levels significantly decreased by injection of both doses of Shilajit and pioglitazone (P<0.05). Increases in serum glucose level and homeostasis model of HOMA-IR were reduced by L-Sh and H-Sh treatment in NAFLD rats (P<0.05). Both doses of Shilajit increased adiponectin and decreased serum resistin levels (P<0.05).

Conclusion

The probable protective role of Shilajit in NAFLD model rats may be via modulating the serum levels of IL-1β, TNF-α, IL-10, adipokine and resistin, and reducing of HOMA-IR.

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.

Similar content being viewed by others

References

  1. Effendi K, Harada K, Hashimoto E, Kage M, Koike K, Kondo F, et al. Pathological findings of NASH and NAFLD: for guidebook of NASH and NAFLD, 2015: The Japan Society of Hepatology. Hepatol Res 2017;47:3–10.

    Article  Google Scholar 

  2. Younossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry L, Wymer M. Global epidemiology of nonalcoholic fatty liver disease—meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology 2016;64:73–84.

    Article  PubMed  Google Scholar 

  3. Alam S, Mustafa G, Alam M, Ahmad N. Insulin resistance in development and progression of nonalcoholic fatty liver disease. World J Gastrointest Pathophysiol 2016;7:211.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Boden G, Homko C, Barrero CA, Stein TP, Chen X, Cheung P, et al. Excessive caloric intake acutely causes oxidative stress, GLUT4 carbonylation, and insulin resistance in healthy men. Sci Transl Med 2015;7:304–307.

    Article  CAS  Google Scholar 

  5. 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 

  6. Zhang Z, Wang J, Wang H. Correlation of blood glucose, serum chemerin and insulin resistance with NAFLD in patients with type 2 diabetes mellitus. Exper Therap Med 2018;15:2936–2940.

    CAS  Google Scholar 

  7. Utzschneider KM, Kahn SE. The role of insulin resistance in nonalcoholic fatty liver disease. J Clin Endocrinol Metab 2006;91:4753–4761.

    Article  CAS  PubMed  Google Scholar 

  8. Sekizkardes H, Chung ST, Chacko S, Haymond MW, Startzell M, Walter M, et al. Free fatty acid processing diverges in human pathologic insulin resistance conditions. J Clin Invest 2020;130. DOI: https://doi.org/10.1172/JCI135431.

  9. Matthews D, Hosker J, Rudenski A, Naylor B, Treacher D, Turner R. Homeostasis model assessment: insulin resistance and β-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985;28:412–419.

    Article  CAS  PubMed  Google Scholar 

  10. Fujii H, Imajo K, Yoneda M, Nakahara T, Hyogo H, Takahashi H, et al. HOMA-IR: an independent predictor of advanced liver fibrosis in nondiabetic non-alcoholic fatty liver disease. J Gastroenterol Hepatol 2019;34:1390–1395.

    Article  CAS  PubMed  Google Scholar 

  11. Saltiel AR, Olefsky JM. Inflammatory mechanisms linking obesity and metabolic disease. J Clin Invest 2017;127:1–4.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Yki-Järvinen H, ed. Pathogenesis of nonalcoholic fatty liver disease (NAFLD). Chichester: John Wiley Sons, Ltd; 2015:281–291.

    Google Scholar 

  13. Imam SK, ed. White adipose tissue: beyond fat storage. Obesity: Springer; 2016:1–12.

    Google Scholar 

  14. Jung UJ, Choi MS. Obesity and its metabolic complications: the role of adipokines and the relationship between obesity, inflammation, insulin resistance, dyslipidemia and nonalcoholic fatty liver disease. Int J Mol Sci 2014;15:6184–6223.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Tarantino G, Savastano S, Colao A. Hepatic steatosis, low-grade chronic inflammation and hormone/growth factor/adipokine imbalance. World J Gastroenterol 2010;16:4773.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Stojsavljevic S, Paléic MG, Jukic LV, Duvnjak LS, Duvnjak M. Adipokines and proinflammatory cytokines, the key mediators in the pathogenesis of nonalcoholic fatty liver disease. World J Gastroenterol 2014;20:18070.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Jamali R, Hatami N, Kosari F. The correlation between serum adipokines and liver cell damage in non-alcoholic fatty liver disease. Hepat Mon 2016;16:e37412.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Matsuzawa Y. Adiponectin: a key player in obesity related disorders. Curr Pharm Des 2010;16:1896–1901.

    Article  CAS  PubMed  Google Scholar 

  19. Pant K, Gupta P, Damania P, Yadav AK, Gupta A, Ashraf A, et al. Mineral pitch induces apoptosis and inhibits proliferation via modulating reactive oxygen species in hepatic cancer cells. BMC Complement Altern Med 2016;16:148.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Thatte UM, Gogtay NJ. Traditional medicine: a review of work in India (2012–2017). Proc Indian Nat Sci Acad 2018;84:267–279.

    Google Scholar 

  21. Carrasco-Gallardo C, Guzmán L, Maccioni RB. Shilajit: a natural phytocomplex with potential procognitive activity. Int J Alzheimer’s Dis 2012;2012:674142.

    Google Scholar 

  22. Ghaaazi Firozsalari F, Shahrokhi N, Khaksari Hadad M, Asadikaram G, Atashbar J. Effect of Shilajit on the levels of pro-inflammatory and anti-inflammation cytokines in hepatic injury in male rats. J Mazandaran Univer Med Sci 2018;27:1–13.

    Google Scholar 

  23. Verma A. Shilajitin cancer treatment: probable mode of action. Int J Pharm Biol Arch 2015;7:12–16.

    Google Scholar 

  24. Moghadari M, Rezvanipour M, Mehrabani M, Ahmadinejad M, Tajadini H, Hashempur MH. Efficacy of mummy on healing of pressure ulcers: a randomized controlled clinical trial on hospitalized patients in intensive care unit. Electronic Phys 2018;10:6140.

    Article  Google Scholar 

  25. Trivedi N, Mazumdar B, Bhatt J, Hemavathi K. Effect of Shilajit on blood glucose and lipid profile in alloxan-induced diabetic rats. Indian J Pharmacol 2004;36:373.

    CAS  Google Scholar 

  26. Jafari M, Forootanfar H, Ameri A, Foroutanfar A, Adeli-Sardou M, Rahimi HR, et al. Antioxidant, cytotoxic and hyperalgesia-suppressing activity of a native Shilajit obtained from Bahr Aseman mountains. Pakistan J Pharm Sci 2019;32:2167–2173.

    CAS  Google Scholar 

  27. Masarone M, Rosato V, Dallio M, Gravina AG, Aglitti A, Loguercio C, et al. Role of oxidative stress in pathophysiology of nonalcoholic fatty liver disease. Oxid Med Cell Longev 2018;2018:9547613–9547613.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Deng XQ, Chen LL, Li NX. The expression of SIRT1 in nonalcoholic fatty liver disease induced by high-fat diet in rats. Liver Int 2007;27:708–715.

    Article  CAS  PubMed  Google Scholar 

  29. Khaksari M, Mahmmodi R, Shahrokhi N, Shabani M, Joukar S, Aqapour M. The effects of Shilajit on brain edema, intracranial pressure and neurologic outcomes following the traumatic brain injury in rat. Iran J Basic Med Sci 2013;16:858.

    PubMed  PubMed Central  Google Scholar 

  30. Pasarín M, Abraldes JG, Rodríguez-Vilarrupla A, La Mura V, García-Pagán JC, Bosch J. Insulin resistance and liver microcirculation in a rat model of early NAFLD. J Hepatol 2011;55:1095–1102.

    Article  PubMed  CAS  Google Scholar 

  31. Ghezelbash B, Shahrokhi N, Khaksari M, Ghaderi-Pakdel F, Asadikaram G. Hepatoprotective effects of Shilajit on high fat-diet induced non-alcoholic fatty liver disease (NAFLD) in rats. Hormone Mol Bio Clin Invest 2020;41.

  32. Bhattacharaya S. Shilajit attenuates streptozotocin induced diabetes mellitus and decreases pancreatic islet superoxide dismutase activity in rats. Phytother Res 1995;9:41–44.

    Article  Google Scholar 

  33. Kanikkannan N, Ramarao P, Ghosal S. Shilajit-induced potentiation of the hypoglycaemic action of insulin and inhibition of streptozotocin induced diabetes in rat. Phytother Res 1995;9:478–481.

    Article  Google Scholar 

  34. Braunersreuther V, Viviani GL, Mach F, Montecucco F. Role of cytokines and chemokines in non-alcoholic fatty liver disease. World J Gastroenterol 2012;18:727.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Del Campo JA, Gallego P, Grande L. Role of inflammatory response in liver diseases: therapeutic strategies. World J Hepatol 2018;10:1.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Mirea AM, Tack CJ, Chavakis T, Joosten LA, Toonen EJ. IL-1 family cytokine pathways underlying NAFLD: towards new treatment strategies. Trends Mol Med 2018;24:458–471.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Li Z, Li Y, Zhang HX, Guo JR, Lam CWK, Wang CY, et al. Mitochondria-mediated pathogenesis and therapeutics for non-alcoholic fatty liver disease. Mol Nutrit Food Res 2019;63:1900043.

    Article  CAS  Google Scholar 

  38. Niederreiter L, Tilg H. Cytokines and fatty liver diseases. Liver Res 2018;2:14–20.

    Article  Google Scholar 

  39. Kern PA, Ranganathan S, Li C, Wood L, Ranganathan G. Adipose tissue tumor necrosis factor and interleukin-6 expression in human obesity and insulin resistance. Am J Physiol Endocrinol Metab 2001;280:E745–E751.

    Article  CAS  PubMed  Google Scholar 

  40. Fernandez-Real JM, Vayreda M, Richart C, Gutierrez C, Broch M, Vendrell J, et al. Circulating interleukin 6 levels, blood pressure, and insulin sensitivity in apparently healthy men and women. J Clin Endocrinol Metab 2001;86:1154–1159.

    Article  CAS  PubMed  Google Scholar 

  41. Shahrokhi N, Keshavarzi Z, Haddad MK, Amirafzali F, Dabiri S, Shahrokhi N. Protective effect of Mumiju against acetic acid-induced ulcerative colitis in rats. Avicenna J Phytomed 2018;8:457.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Mirza MA, Talegaonkar S, Ahmad FJ, Iqbal Z. A novel and multifunctional excipient for vaginal drug delivery. J Excipients Food Chem 2016;2:1119.

    Google Scholar 

  43. Wang Q, Ying J, Zou P, Zhou Y, Wang B, Yu D, et al. Effects of dietary supplementation of humic acid sodium and zinc oxide on growth performance, immune status antioxidant capacity weaned piglets. Animals 2020;10:2104.

    Article  PubMed Central  Google Scholar 

  44. van Rensburg CEJ, Naude PJ. Potassium humate inhibits complement activation and the production of inflammatory cytokines in vitro. Inflammation 2009;32:270–276.

    Article  PubMed  CAS  Google Scholar 

  45. Boutari C, Perakakis N, Mantzoros CS. Association of adipokines with development and progression of nonalcoholic fatty liver disease. Endocrinol Metab 2018;33:33–43.

    Article  CAS  Google Scholar 

  46. Singh R, Moreno P, Hajjar RJ, Lebeche D. A role for calcium in resistin transcriptional activation in diabetic hearts. Sci Rep 2018;8:1–14.

    Google Scholar 

  47. Pagano C, Soardo G, Pilon C, Milocco C, Basan L, Milan G, et al. Increased serum resistin in nonalcoholic fatty liver disease is related to liver disease severity and not to insulin resistance. J Clin Endocrinol Metab 2006;91:1081–1086.

    Article  CAS  PubMed  Google Scholar 

  48. Adolph T, Grander C, Grabherr F, Tilg H. Adipokines and non-alcoholic fatty liver disease: multiple interactions. Intern J Molecular Sci 2017;18:1649.

    Article  CAS  Google Scholar 

  49. Colica C, Abenavoli L. Resistin levels in non-alcoholic fatty liver disease pathogenesis. J Transl Inter Med 2018;6:52–53.

    Article  Google Scholar 

  50. Finelli C, Tarantino G. What is the role of adiponectin in obesity related non-alcoholic fatty liver disease? World J Gastroenterol 2013;19:802–812.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Gamberi T, Magherini F, Modesti A, Fiaschi T. Adiponectin signaling pathways in liver diseases. Biomedicines 2018;6:52.

    Article  PubMed Central  CAS  Google Scholar 

  52. Ishtiaq SM, Rashid H, Hussain Z, Arshad MI, Khan JA. Adiponectin and PPAR: a setup for intricate crosstalk between obesity and non-alcoholic fatty liver disease. Rev Endoc Metab Disord 2019;20:253–261.

    Article  CAS  Google Scholar 

  53. Xu A, Wang Y, Keshaw H, Xu LY, Lam KS, Cooper GJ. The fat-derived hormone adiponectin alleviates alcoholic and nonalcoholic fatty liver diseases in mice. J Clin Invest 2003;112:91–100.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Tilg H. The role of cytokines in non-alcoholic fatty liver disease. Digest Dis 2010;28:179–185.

    Article  CAS  Google Scholar 

Download references

Acknowledgment

This study is part of a PhD degree dissertation in Physiology. Authors are grateful for support of the administrators at Physiology Research Center and Kerman University of Medical Science, Kerman, Iran.

Author information

Authors and Affiliations

Authors

Contributions

Ghezelbash B conducted research and provided assistance in writing the paper and data analysis. Shahrokhi N designed research, analyzed data and wrote the paper. Khaksari M and Asadikaram G contributed to paper writing and data analysis. Shahrokhi M and Shirazpour S contributed new reagents/analytic tools and wrote the paper.

Corresponding author

Correspondence to Nader Shahrokhi.

Additional information

Conflict of Interest

Authors declare no conflict of interest.

Supported by Department of Physiology and Pharmacology, Kerman University of Medical Sciences, Kerman, Iran

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ghezelbash, B., Shahrokhi, N., Khaksari, M. et al. Protective Roles of Shilajit in Modulating Resistin, Adiponectin, and Cytokines in Rats with Non-alcoholic Fatty Liver Disease. Chin. J. Integr. Med. 28, 531–537 (2022). https://doi.org/10.1007/s11655-022-3307-3

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11655-022-3307-3

Keywords

Navigation