Skip to main content

Advertisement

Log in

Role of Cytokines in the Pathogenesis of Non-Alcoholic Fatty Liver Disease

  • Original Article
  • Published:
Indian Journal of Clinical Biochemistry Aims and scope Submit manuscript

Abstract

A number of factors are linked with non-alcoholic fatty liver diseases (NAFLD), a condition that ranges from clinically benign fatty liver to its more severe form, non alcoholic steatohepatitis (NASH). In this study, we evaluated the role of cytokines secreted from adipose tissue in the pathogenesis and progression of NAFLD. We also compared anthropometric profile, lipid profile and insulin resistance data in 105 NAFLD patients with 77 normal subjects. These subjects showed a normal serum albumin level, prothrombin time and renal function but elevated aminotransferases. Predisposing factors were diabetes mellitus (35%), overweight (56%) and hyperlipidemia (44%). Insulin resistance (IR), determined by homeostasis model assessment (HOMA) was confirmed in 70% patients with NAFLD and 42% patients fulfilled the minimum criteria for insulin resistance syndrome (IRS). NAFLD patients showed elevated levels of pro-inflammatory cytokines tumor necrosis factor (TNF)-α, and interleukin (IL)-6, while anti-inflammatory cytokines IL-4 level decreased and IL-10 level remain unchanged; however, TGF-β1 level elevated significantly compared to normal subjects. While insulin level and HOMA-IR both were significantly positively correlated with BMI, waist-to-hip ratio, total cholesterol, VLDL-cholesterol, triglyceride and TGF-β1; glucose, IL-6 and TNF-α levels were significantly positively correlated with HOMA-IR only. In conclusion, pro-inflammatory cytokines play an important link between metabolic and liver disorders in the fat accumulation, and thereby cause IR, inflammation and liver fibrosis.

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.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Bugianesi E, McCullough AJ, Marchesini G. Insulin resistance: a metabolic pathway to chronic liver disease. Hepatology. 2005;42(5):987–1000.

    Article  PubMed  CAS  Google Scholar 

  2. Ludwig J, Viggiano TR, McGill DB, Ott BJ. Nonalcoholic steatohepatitis: Mayo Clinic experiences with a hitherto unnamed disease. Mayo Clin Proc. 1980;55:434–8.

    PubMed  CAS  Google Scholar 

  3. Das SK, Balakrishnan V, Mukherjee S, Vasudevan DM. Evaluation of blood oxidative stress related parameters in alcoholic liver disease and non-alcoholic fatty liver disease. Scand J Clin Lab Invest. 2008;68(4):323–34.

    Article  PubMed  CAS  Google Scholar 

  4. Das SK, Mukherjee S, Vasudevan DM. Non-alcoholic fatty liver diseases: an under recognized cause with emerging importance. Current Sci. 2006;90:659–65.

    CAS  Google Scholar 

  5. Fan JG, Zhu J, Li XJ, Chen L, Li L, Dai F, Li F, Chen SY. Prevalence of and risk factors for fatty liver in a general population of Shanghai, China. J Hepatol. 2005;43:508–14.

    Article  PubMed  Google Scholar 

  6. Diehl AM, Li ZP, Lin HZ, Yang SQ. Cytokines and the pathogenesis of non-alcoholic steatohepatitis. Gut. 2005;54(2):303–6.

    Article  PubMed  CAS  Google Scholar 

  7. Browning JD, Horton JD. Molecular mediators of hepatic steatosis and liver injury. J Clin Invest. 2004;114:147–52.

    PubMed  CAS  Google Scholar 

  8. Day CP, James OF. Steatohepatitis—a tale of two hits. Gastroenterology. 1998;114:842–5.

    Article  PubMed  CAS  Google Scholar 

  9. McClain CJ, Mokshagundam SP, Barve SS, et al. Mechanisms of non-alcoholic steatohepatitis. Alcohol. 2004;34:67–79.

    Article  PubMed  CAS  Google Scholar 

  10. Ma KL, Ruan XZ, Powis SH, Chen Y, Moorhead JF, Varghese Z. Inflammatory stress exacerbates lipid accumulation in hepatic cells and fatty livers of apolipoprotein E knockout mice. Hepatology. 2008;48(3):770–81.

    Article  PubMed  CAS  Google Scholar 

  11. Drenick EJ, Fisler J, Johnson D. Hepatic steatosis after intestinal bypass—prevention and reversal by metronidazole, irrespective of protein-calorie malnutrition. Gastroenterology. 1982;82:535–48.

    PubMed  CAS  Google Scholar 

  12. Crews FT, Bechara R, Brown LA, Guidot DM, Mandrekar P, Oak S, Qin L, Szabo G, Wheeler M, Zou J. Cytokines and alcohol. Alcohol Clin Exp Res. 2006;30:720–30.

    Article  PubMed  CAS  Google Scholar 

  13. Cameron RG, Neuman MG. Novel morphologic findings in alcoholic liver disease. Clin Biochem. 1999;32(7):579–84.

    Article  PubMed  CAS  Google Scholar 

  14. Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and beta cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia. 1985;28:412–9.

    Article  PubMed  CAS  Google Scholar 

  15. World Health Organization. Consultation. Definition, diagnosis and classification of diabetes mellitus and its complications. Geneva: World Health Organization; 1999. Report No. WHO/NCD/NCS/99.2.

  16. Das SK, Mukherjee S, Pandey G, Balakrishnan V, Vasudevan DM. Clinicopathological spectrum of non-alcoholic fatty liver disease among patients in Kerala. Indian J Clin Biochem. 2009;24(2):155–8.

    Article  Google Scholar 

  17. Angulo P, Hui JM, Marchesini G, Bugianesi E, George J, Farrell GC, et al. The NAFLD fibrosis score: a noninvasive system that identifies liver fibrosis in patients with NAFLD. Hepatology. 2007;45:846–54.

    Article  PubMed  CAS  Google Scholar 

  18. Ko GT, Wu MM, Tang J, Wai HP, Chan CH, Chen R. Body mass index profile in Hong Kong Chinese adults. Ann Acad Med Singapore. 2001;21(1):17–26.

    Google Scholar 

  19. Falck-Ytter Y, Younossi ZM, Marchesini G, McCullough AJ. Clinical features and natural history of nonalcoholic steatosis syndromes. Semin Liver Dis. 2001;21(1):17–26.

    Article  PubMed  CAS  Google Scholar 

  20. Lee K, Sung JA, Kim JS, Park TJ. The roles of obesity and gender on the relationship between metabolic risk factors and non-alcoholic fatty liver disease in Koreans. Diabetes Metab Res Rev. 2009;25(2):150–5.

    Article  PubMed  CAS  Google Scholar 

  21. Marchesini G, Bugianesi E, Forlani G, Cerrelli F, Lenzi M, Manini R, et al. Non alcoholic fatty liver, Steatohepatitis and the metabolic syndrome. Hepatology. 2003;37:917–23.

    Article  PubMed  Google Scholar 

  22. Wilfred de Alwis NM, Day CP. Genetics of alcoholic liver disease and nonalcoholic fatty liver disease. Semin Liver Dis. 2007;27:44–54.

    Article  PubMed  Google Scholar 

  23. Weston SR, Leyden W, Murphy R, Bass NM, Bell BP, Manos MM, Terrault NA. Racial and ethnic distribution of nonalcoholic fatty liver in persons with newly diagnosed chronic liver disease. Hepatology. 2005;41:372–9.

    Article  PubMed  Google Scholar 

  24. Madan K, Batra Y, Gupta SD, Chander B, Rajan KD, Tewatia MS, et al. Non-alcoholic fatty liver disease may not be a severe disease at presentation among Asian Indians. World J Gastroenterol. 2006;12:3400–5.

    PubMed  Google Scholar 

  25. Lee S, Jin Kim Y, Yong Jeon T, Hoi Kim H, Woo Oh S, Park Y, Soo Kim S. Obesity is the only independent factor associated with ultrasound-diagnosed non-alcoholic fatty liver disease: a cross-sectional case-control study. Scand J Gastroenterol. 2006;41(5):566–72.

    Article  PubMed  Google Scholar 

  26. Marchesini G, Brizi M, Morselli-Labate AM, Bianchi G, Bugianesi E, McCullough AJ, et al. Association of non alcoholic fatty liver disease with insulin resistance. Am J Med. 1999;107:450–5.

    Article  PubMed  CAS  Google Scholar 

  27. Chitturi S, Abeygunasekera S, Farrell GC, Holmes-Walker J, Hui JM, Fung C, et al. NASH and insulin resistance: insulin hypersecretion and specific association with the insulin resistance syndrome. Hepatology. 2002;35:373–9.

    Article  PubMed  CAS  Google Scholar 

  28. Muoio DM, Negward CB. Molecular and metabolic mechanisms of insulin resistance and β-cell failure in type 2 diabetes. Nat Rev Mol Cell Biol. 2008;9:193–205.

    Article  PubMed  CAS  Google Scholar 

  29. Verges B. Insulin sensitiviy and lipids. Diabetes Metab. 2001;27(2 Pt 2):223–7.

    PubMed  CAS  Google Scholar 

  30. Kojima H, Sakurai S, Uemura M, Takekawa T, Morimoto H, Tamagawa Y, Fukui H. Difference and similarity between nonalcoholic steatohepatitis and alcoholic liver disease. Alcohol Clin Exp Res. 2005;29(Suppl 12):259S–63S.

    Article  PubMed  Google Scholar 

  31. Ratziu V, Giral P, Charlotte F, Bruckert E, Thibault V, Theodorou I, et al. Liver fibrosis in overweight patients. Gastroenterology. 2000;118:1117–23.

    Article  PubMed  CAS  Google Scholar 

  32. Loguercio C, De Girolamo V, de Sio I, Tuccillo C, Ascione A, Baldi F, et al. Non-alcoholic fatty liver disease in an area of southern Italy: main clinical, histological, and pathophysiological aspects. J Hepatol. 2001;35:568–74.

    Article  PubMed  CAS  Google Scholar 

  33. Tiniakos DG, Vos MB, Brunt EM. Nonalcoholic fatty liver disease: pathology and pathogenesis. Annu Rev Pathol. 2010;5:145–71.

    Article  PubMed  CAS  Google Scholar 

  34. Clark JM, Diehl AM. Nonalcoholic fatty liver disease: an underrecognized cause of cryptogenic cirrhosis. JAMA. 2003;289(22):3000–4.

    Article  PubMed  Google Scholar 

  35. Tilg H, Moschen AR. Inflammatory mechanisms in the regulation of insulin resistance. Mol Med. 2008;14(3–4):222–31.

    PubMed  CAS  Google Scholar 

  36. Polyzos SA, Kountouras J, Zavos C. Nonalcoholic fatty liver disease: the pathogenetic roles of insulin resistance and adipocytokines. Curr Mol Med. 2009;9(3):299–314.

    Article  PubMed  CAS  Google Scholar 

  37. Kim JK, Kim YJ, Fillmore JJ, Chen Y, Moore I, Lee J, et al. Prevention of fat-induced insulin resistance by salicylate. J Clin Invest. 2001;108:437–46.

    PubMed  CAS  Google Scholar 

  38. Kuglemas M, Hill D, Vivian B, Marsano L, McClain C. Cytokines and NASH: a pilot study of the effects of lifestyle modification and vitamin E. Hepatology. 2003;38:413–9.

    Article  Google Scholar 

  39. Wigg AJ, Roberts-Thomson IC, Dymock RB, McCarthy PJ, Grose RH, Cummins AG. The role of small intestinal bacterial overgrowth, intestinal permeability, endotoxaemia, and tumor necrosis factor alpha in the pathogenesis of non-alcoholic steatohepatitis. Gut. 2001;48:206–11.

    Article  PubMed  CAS  Google Scholar 

  40. Fon Tacer K, Kuzman D, Seliskar M, Pompon D, Rozman D. TNF-alpha interferes with lipid homeostasis and activates acute and proatherogenic processes. Physiol Genomics. 2007;31(2):216–27.

    Article  PubMed  Google Scholar 

  41. Feingold KR, Soued M, Serio MK, Adi S, Moser AH, Grunfeld C. The effect of diet on tumor necrosis factor stimulation of hepatic lipogenesis. Metabolism. 1990;39(6):623–32.

    Article  PubMed  CAS  Google Scholar 

  42. Grunfeld C, Feingold KR. Tumor necrosis factor, interleukin, and interferon induced changes in lipid metabolism as part of host defense. Proc Soc Exp Biol Med. 1992;200:224–7.

    PubMed  CAS  Google Scholar 

  43. Wullaert A, van Loo G, Heyninck K, Beyaert R. Hepatic tumor necrosis factor signaling and nuclear factor-kappaB: effects on liver homeostasis and beyond. Endocr Rev. 2007;28(4):365–86.

    Article  PubMed  CAS  Google Scholar 

  44. Tomita K, Tamiya G, Ando S, Ohsumi K, Chiyo T, Mizutani A, et al. Tumour necrosis factor alpha signalling through activation of Kupffer cells plays an essential role in liver fibrosis of non-alcoholic steatohepatitis in mice. Gut. 2006;55(3):415–24.

    Article  PubMed  CAS  Google Scholar 

  45. Papanicolaou DA, Wilder RL, Manolagas SC, Chrousos GP. The pathophysiologic roles of interleukin-6 in human disease. Ann Intern Med. 1998;128:127–37.

    PubMed  CAS  Google Scholar 

  46. Sehgal PB, Greininger G, Tosato G. Regulation of the acute phase and immune responses: interleukin 6. Ann NY Acad Sci. 1989;557:1–583.

    Google Scholar 

  47. Brass EP, Vetter WH. Interleukin-6, but not tumour necrosis factor-alpha, increases lipogenesis in rat hepatocyte primary cultures. Biochem J. 1994;301(Pt 1):193–7.

    PubMed  CAS  Google Scholar 

  48. Fernandez-Real JM, Ricart W. Insulin resistance and chronic cardiovascular inflammatory syndrome. Endocr Rev. 2003;24:278–301.

    Article  PubMed  CAS  Google Scholar 

  49. Kim HJ, Higashimori T, Park SY, Choi H, Dong J, Kim YJ, et al. Differential effects of interleukin-6 and -10 on skeletal muscle and liver insulin action in vivo. Diabetes. 2004;53(4):1060–7.

    Article  PubMed  CAS  Google Scholar 

  50. Hotamisligil GS. Inflammatory pathways and insulin action. Int J Obes Relat Metab Disord. 2003;27(Suppl 3):S53–5.

    Article  PubMed  CAS  Google Scholar 

  51. Senn JJ, Klover PJ, Nowak IA, Mooney RA. IL-6 induces insulin resistance in hepatocytes. Diabetes. 2002;51:3391–9.

    Article  PubMed  CAS  Google Scholar 

  52. Bastard JP, Maachi M, Lagathu C, Kim MJ, Caron M, Vidal H, Capeau J, Feve B. Recent advances in the relationship between obesity, inflammation, and insulin resistance. Eur Cytokine Netw. 2006;17(1):4–12.

    PubMed  CAS  Google Scholar 

  53. Skapenko A, Niedobitek GU, Kalden JR, Lipsky PE, Schulze-Koops H. Generation and regulation of human Th1-biased immune responses in vivo: a critical role for IL-4 and IL-10. J Immunol. 2004;172(10):6427–34.

    PubMed  CAS  Google Scholar 

  54. Cintra DE, Pauli JR, Araújo EP, Moraes JC, de Souza CT, Milanski M, et al. Interleukin-10 is a protective factor against diet-induced insulin resistance in liver. J Hepatol. 2008;48(4):628–37.

    PubMed  CAS  Google Scholar 

  55. Tarantino G, Conca P, Riccio A, Tarantino M, Di Minno MN, Chianese D, et al. Enhanced serum concentrations of transforming growth factor-beta1 in simple fatty liver: is it really benign? J Transl Med. 2008;6:72.

    Google Scholar 

Download references

Acknowledgments

Financial assistance received from Van Slyke Foundation-Critical and Point-of-Care Testing (VSF-CPOCT) Research Grant; American Association for Clinical Chemistry is gratefully acknowledged.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Subir Kumar Das.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOC 44 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Das, S.K., Balakrishnan, V. Role of Cytokines in the Pathogenesis of Non-Alcoholic Fatty Liver Disease. Ind J Clin Biochem 26, 202–209 (2011). https://doi.org/10.1007/s12291-011-0121-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12291-011-0121-7

Keywords

Navigation