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.
Similar content being viewed by others
References
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.
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.
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.
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.
Sears B, Perry M. The role of fatty acids in insulin resistance. Lipids Health Dis 2015;14:121.
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.
Utzschneider KM, Kahn SE. The role of insulin resistance in nonalcoholic fatty liver disease. J Clin Endocrinol Metab 2006;91:4753–4761.
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.
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.
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.
Saltiel AR, Olefsky JM. Inflammatory mechanisms linking obesity and metabolic disease. J Clin Invest 2017;127:1–4.
Yki-Järvinen H, ed. Pathogenesis of nonalcoholic fatty liver disease (NAFLD). Chichester: John Wiley Sons, Ltd; 2015:281–291.
Imam SK, ed. White adipose tissue: beyond fat storage. Obesity: Springer; 2016:1–12.
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.
Tarantino G, Savastano S, Colao A. Hepatic steatosis, low-grade chronic inflammation and hormone/growth factor/adipokine imbalance. World J Gastroenterol 2010;16:4773.
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.
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.
Matsuzawa Y. Adiponectin: a key player in obesity related disorders. Curr Pharm Des 2010;16:1896–1901.
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.
Thatte UM, Gogtay NJ. Traditional medicine: a review of work in India (2012–2017). Proc Indian Nat Sci Acad 2018;84:267–279.
Carrasco-Gallardo C, Guzmán L, Maccioni RB. Shilajit: a natural phytocomplex with potential procognitive activity. Int J Alzheimer’s Dis 2012;2012:674142.
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.
Verma A. Shilajitin cancer treatment: probable mode of action. Int J Pharm Biol Arch 2015;7:12–16.
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.
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.
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.
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.
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.
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.
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.
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.
Bhattacharaya S. Shilajit attenuates streptozotocin induced diabetes mellitus and decreases pancreatic islet superoxide dismutase activity in rats. Phytother Res 1995;9:41–44.
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.
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.
Del Campo JA, Gallego P, Grande L. Role of inflammatory response in liver diseases: therapeutic strategies. World J Hepatol 2018;10:1.
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.
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.
Niederreiter L, Tilg H. Cytokines and fatty liver diseases. Liver Res 2018;2:14–20.
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.
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.
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.
Mirza MA, Talegaonkar S, Ahmad FJ, Iqbal Z. A novel and multifunctional excipient for vaginal drug delivery. J Excipients Food Chem 2016;2:1119.
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.
van Rensburg CEJ, Naude PJ. Potassium humate inhibits complement activation and the production of inflammatory cytokines in vitro. Inflammation 2009;32:270–276.
Boutari C, Perakakis N, Mantzoros CS. Association of adipokines with development and progression of nonalcoholic fatty liver disease. Endocrinol Metab 2018;33:33–43.
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.
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.
Adolph T, Grander C, Grabherr F, Tilg H. Adipokines and non-alcoholic fatty liver disease: multiple interactions. Intern J Molecular Sci 2017;18:1649.
Colica C, Abenavoli L. Resistin levels in non-alcoholic fatty liver disease pathogenesis. J Transl Inter Med 2018;6:52–53.
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.
Gamberi T, Magherini F, Modesti A, Fiaschi T. Adiponectin signaling pathways in liver diseases. Biomedicines 2018;6:52.
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.
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.
Tilg H. The role of cytokines in non-alcoholic fatty liver disease. Digest Dis 2010;28:179–185.
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
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
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
About this article
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
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11655-022-3307-3