Is Melatonin Associated with Pro-Inflammatory Cytokine Activity and Liver Fibrosis in Non-Alcoholic Fatty Liver Disease (NAFLD) Patients? Melatonin & Cytokines in NAFLD
Gastroenterology and Hepatology from Bed to Bench,
26 April 2021
The associations between serum levels of melatonin and concentrations of tumor necrosis factor (TNF)-a and interleukin (IL)-6 were assessed among patients with different degrees of non-alcoholic fatty liver diseases.
In this cross-sectional study, adult patients diagnosed with fatty liver disease by Fibroscan evaluation were included if they met the inclusion/exclusion criteria for NAFLD. The participants were categorized into the three following groups: 1) fibrosis> 9.1KP and steatosis>290 dbm; 2) fibrosis: 6-9.0 KP and steatosis 240-285; and 3) fibrosis< 5.8 KP and steatosis<240 dbm. Post-fasting, 5 ml of venous blood was collected for laboratory assessment, and a questionnaire including demographic, anthropometric, laboratories and clinical data were completed.
A total 97 participants were included. The mean age was 42.21±11 years old. 59 patients (60.0%) were female. Melatonin levels, as well as pro-inflammatory cytokines levels, correlated with advancing fibrosis and steatosis in the univariate analysis. A significant association was observed between these cytokines and advancing fibrosis, severe steatosis levels and melatonin concentrations. Furthermore, in the multiple linear regression model, melatonin levels showed a significant association with these cytokines.
Melatonin may have protective effects on tissue injury during advancing liver fibrosis via cytokines modulation. Therefore, it can be considered as a potential therapeutic management strategy for NAFLD .
Key words: Fatty liver, Cytokine, Melatonin, Inflammation
- Fatty liver
2. Bessone F, Razori MV, Roma MG. Molecular pathways of nonalcoholic fatty liver disease development and progression. 2019;76(1):99-128.
3. Haas JT, Francque S, Staels B. Pathophysiology and Mechanisms of Nonalcoholic Fatty Liver Disease. Annual review of physiology. 2016;78:181-205.
4. Buzzetti E, Pinzani M, Tsochatzis EA. The multiple-hit pathogenesis of non-alcoholic fatty liver disease (NAFLD). Metabolism: clinical and experimental. 2016;65(8):1038-48.
5. Rehman K, Akash MS. Mechanisms of inflammatory responses and development of insulin resistance: how are they interlinked? 2016;23(1):87.
6. Moschen AR, Molnar C, Geiger S, Graziadei I, Ebenbichler CF, Weiss H, et al. Anti-inflammatory effects of excessive weight loss: potent suppression of adipose interleukin 6 and tumour necrosis factor alpha expression. Gut. 2010;59(9):1259-64.
7. Netea MG, Balkwill F, Chonchol M, Cominelli F, Donath MY, Giamarellos-Bourboulis EJ. A guiding map for inflammation. 2017;18(8):826-31.
8. Crews FT, Bechara R, Brown LA, Guidot DM, Mandrekar P, Oak S, et al. Cytokines and alcohol. Alcoholism, clinical and experimental research. 2006;30(4):720-30.
9. Li Z, Yang S, Lin H, Huang J, Watkins PA, Moser AB, et al. Probiotics and antibodies to TNF inhibit inflammatory activity and improve nonalcoholic fatty liver disease. Hepatology (Baltimore, Md). 2003;37(2):343-50.
10. Bali İ, Bilir B, Emir S, Turan F, Yılmaz A, Gökkuş T, et al. The effects of melatonin on liver functions in arsenic-induced liver damage. Ulusal cerrahi dergisi. 2016;32(4):233-7.
11. Das SK, Balakrishnan V. Role of cytokines in the pathogenesis of non-alcoholic Fatty liver disease. Indian journal of clinical biochemistry : IJCB. 2011;26(2):202-9.
12. Assunção SNF, Sorte N, Alves CAD, Mendes PSA, Alves CRB, Silva LR. Inflammatory cytokines and non-alcoholic fatty liver disease (NAFLD) in obese children and adolescents. Nutricion hospitalaria. 2018;35(1):78-83.
13. Slominski A, Tobin DJ, Zmijewski MA, Wortsman J, Paus R. Melatonin in the skin: synthesis, metabolism and functions. Trends in endocrinology and metabolism: TEM. 2008;19(1):17-24.
14. El-Sokkary GH, Nafady AA, Shabash EH. Melatonin administration ameliorates cadmium-induced oxidative stress and morphological changes in the liver of rat. Ecotoxicology and environmental safety. 2010;73(3):456-63.
15. Esteban-Zubero E, Alatorre-Jiménez MA, López-Pingarrón L, Reyes-Gonzales MC, Almeida-Souza P, Cantín-Golet A, et al. Melatonin's role in preventing toxin-related and sepsis-mediated hepatic damage: A review. Pharmacological research. 2016;105:108-20.
16. Wong VW, Petta S, Hiriart JB, Cammà C, Wong GL, Marra F, et al. Validity criteria for the diagnosis of fatty liver by M probe-based controlled attenuation parameter. Journal of hepatology. 2017;67(3):577-84.
17. Li Y, Li S, Zhou Y, Meng X, Zhang JJ, Xu DP, et al. Melatonin for the prevention and treatment of cancer. Oncotarget. 2017;8(24):39896-921.
18. Sun H, Huang FF, Qu S. Melatonin: a potential intervention for hepatic steatosis. Lipids in health and disease. 2015;14:75.
19. Heo JI, Yoon DW, Yu JH, Kim NH, Yoo HJ, Seo JA, et al. Melatonin improves insulin resistance and hepatic steatosis through attenuation of alpha-2-HS-glycoprotein. 2018;65(2):e12493.
20. Farrell GC, Haczeyni F, Chitturi S. Pathogenesis of NASH: How Metabolic Complications of Overnutrition Favour Lipotoxicity and Pro-Inflammatory Fatty Liver Disease. Advances in experimental medicine and biology. 2018;1061:19-44.
21. Hijmans BS, Grefhorst A, Oosterveer MH, Groen AK. Zonation of glucose and fatty acid metabolism in the liver: mechanism and metabolic consequences. Biochimie. 2014;96:121-9.
22. Tilg H. The role of cytokines in non-alcoholic fatty liver disease. Digestive diseases (Basel, Switzerland). 2010;28(1):179-85.
23. Zhang F, Jiang WW, Li X, Qiu XY, Wu Z, Chi YJ, et al. Role of intrahepatic B cells in non-alcoholic fatty liver disease by secreting pro-inflammatory cytokines and regulating intrahepatic T cells. Journal of digestive diseases. 2016;17(7):464-74.
24. Lambertucci F, Arboatti A, Sedlmeier MG, Motiño O, Alvarez ML, Ceballos MP, et al. Disruption of tumor necrosis factor alpha receptor 1 signaling accelerates NAFLD progression in mice upon a high-fat diet. The Journal of nutritional biochemistry. 2018;58:17-27.
25. Kiagiadaki F, Kampa M, Voumvouraki A, Castanas E, Kouroumalis E, Notas G. Activin-A causes Hepatic stellate cell activation via the induction of TNFα and TGFβ in Kupffer cells. Biochimica et biophysica acta Molecular basis of disease. 2018;1864(3):891-9.
26. Verdam FJ, Rensen SS, Driessen A, Greve JW, Buurman WA. Novel evidence for chronic exposure to endotoxin in human nonalcoholic steatohepatitis. Journal of clinical gastroenterology. 2011;45(2):149-52.
27. du Plessis J, van Pelt J, Korf H, Mathieu C, van der Schueren B, Lannoo M, et al. Association of Adipose Tissue Inflammation With Histologic Severity of Nonalcoholic Fatty Liver Disease. Gastroenterology. 2015;149(3):635-48.e14.
28. du Plessis J, Korf H, van Pelt J, Windmolders P, Vander Elst I, Verrijken A, et al. Pro-Inflammatory Cytokines but Not Endotoxin-Related Parameters Associate with Disease Severity in Patients with NAFLD. PloS one. 2016;11(12):e0166048.
29. Glund S, Krook A. Role of interleukin-6 signalling in glucose and lipid metabolism. Acta physiologica (Oxford, England). 2008;192(1):37-48.
30. Gavito AL, Bautista D, Suarez J, Badran S, Arco R, Pavón FJ, et al. Chronic IL-6 Administration Desensitizes IL-6 Response in Liver, Causes Hyperleptinemia and Aggravates Steatosis in Diet-Induced-Obese Mice. 2016;11(6):e0157956.
31. Yamaguchi K, Itoh Y, Yokomizo C, Nishimura T, Niimi T, Fujii H, et al. Blockade of interleukin-6 signaling enhances hepatic steatosis but improves liver injury in methionine choline-deficient diet-fed mice. Laboratory investigation; a journal of technical methods and pathology. 2010;90(8):1169-78.
32. Vida M, Gavito AL, Pavón FJ, Bautista D, Serrano A, Suarez J, et al. Chronic administration of recombinant IL-6 upregulates lipogenic enzyme expression and aggravates high-fat-diet-induced steatosis in IL-6-deficient mice. Disease models & mechanisms. 2015;8(7):721-31.
33. Kirpich IA, Marsano LS, McClain CJ. Gut-liver axis, nutrition, and non-alcoholic fatty liver disease. Clinical biochemistry. 2015;48(13-14):923-30.
34. Cani PD, Delzenne NM. Interplay between obesity and associated metabolic disorders: new insights into the gut microbiota. Current opinion in pharmacology. 2009;9(6):737-43.
35. Pakravan H, Ahmadian M, Fani A, Aghaee D, Brumanad S, Pakzad B. The Effects of Melatonin in Patients with Nonalcoholic Fatty Liver Disease: A Randomized Controlled Trial. Advanced biomedical research. 2017;6:40.
36. Agil A, El-Hammadi M, Jiménez-Aranda A, Tassi M, Abdo W, Fernández-Vázquez G, et al. Melatonin reduces hepatic mitochondrial dysfunction in diabetic obese rats. Journal of pineal research. 2015;59(1):70-9.
37. Xu P, Wang J, Hong F, Wang S, Jin X, Xue T, et al. Melatonin prevents obesity through modulation of gut microbiota in mice. 2017;62(4).
38. Stacchiotti A, Grossi I. Melatonin Effects on Non-Alcoholic Fatty Liver Disease Are Related to MicroRNA-34a-5p/Sirt1 Axis and Autophagy. 2019;8(9).
39. Xu X, Wang G, Ai L, Shi J, Zhang J, Chen YX. Melatonin suppresses TLR9-triggered proinflammatory cytokine production in macrophages by inhibiting ERK1/2 and AKT activation. Scientific reports. 2018;8(1):15579.
40. Srinivasan V, Spence DW, Pandi-Perumal SR, Trakht I, Cardinali DP. Therapeutic actions of melatonin in cancer: possible mechanisms. Integrative cancer therapies. 2008;7(3):189-203.
41. Zhou LL, Wei W, Si JF, Yuan DP. Regulatory effect of melatonin on cytokine disturbances in the pristane-induced lupus mice. Mediators of inflammation. 2010;2010.
42. Sánchez-López AL, Ortiz GG, Pacheco-Moises FP, Mireles-Ramírez MA, Bitzer-Quintero OK, Delgado-Lara DLC, et al. Efficacy of Melatonin on Serum Pro-inflammatory Cytokines and Oxidative Stress Markers in Relapsing Remitting Multiple Sclerosis. Archives of medical research. 2018;49(6):391-8.
- Abstract Viewed: 0 times