Pediatr Gastroenterol Hepatol Nutr.  2012 Jun;15(2):74-78.

The Role of Inflammatory Mediators in the Pathogenesis of Nonalcoholic Fatty Liver Disease

• Kim JS

Abstract

With a markedly increased prevalence of obesity, non-alcoholic fatty liver disease (NAFLD) now becomes the most common cause of chronic liver disease in both adults and children. The etiology and pathogenesis of NAFLD are multifactorial and remain incompletely understood. According to the "two-hit" theory, inflammatory cytokines and adipokines are activated by oxidative stress and they are involved in insulin resistance, necroinflammatory steatohepatitis and fibrosis. This review discusses the latest updates on the role of some of important inflammatory adipokines and cytokines in the pathogenesis of NAFLD with an emphasis on their potential therapeutic implications.

Keyword

Nonalcoholic fatty liver disease; Obesity; Inflammation; Adipokine; Cytokine; Pathogenesis; Insulin resistance

MeSH Terms

Adipokines
Adult
Child
Cytokines
Fatty Liver
Fibrosis
Humans
Inflammation
Insulin Resistance
Liver Diseases
Obesity
Oxidative Stress
Prevalence
Adipokines
Cytokines
Fatty Liver

Reference

1. Clark JM, Brancati FL, Diehl AM. Nonalcoholic fatty liver disease. Gastroenterology. 2002. 122:1649–1657.

2. Ruhl CE, Everhart JE. Epidemiology of nonalcoholic fatty liver. Clin Liver Dis. 2004. 8:501–519.

3. Farrell GC, Larter CZ. Nonalcoholic fatty liver disease: from steatosis to cirrhosis. Hepatology. 2006. 43:S99–S112.

4. Qureshi K, Abrams GA. Metabolic liver disease of obesity and role of adipose tissue in the pathogenesis of nonalcoholic fatty liver disease. World J Gastroenterol. 2007. 13:3540–3553.

5. Brunt EM, Janney CG, Di Bisceglie AM, Neuschwander-Tetri BA, Bacon BR. Nonalcoholic steatohepatitis: a proposal for grading and staging the histological lesions. Am J Gastroenterol. 1999. 94:2467–2474.

6. McCullough AJ. Update on nonalcoholic fatty liver disease. J Clin Gastroenterol. 2002. 34:255–262.

7. Day CP, James OF. Steatohepatitis: a tale of two "hits"? Gastroenterology. 1998. 114:842–845.

8. Sanyal AJ, Campbell-Sargent C, Mirshahi F, Rizzo WB, Contos MJ, Sterling RK, et al. Nonalcoholic steatohepatitis: association of insulin resistance and mitochondrial abnormalities. Gastroenterology. 2001. 120:1183–1192.

9. Chitturi S, Farrell GC. Etiopathogenesis of nonalcoholic steatohepatitis. Semin Liver Dis. 2001. 21:27–41.

10. Romeo S, Kozlitina J, Xing C, Pertsemlidis A, Cox D, Pennacchio LA, et al. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat Genet. 2008. 40:1461–1465.

11. Santoro N, Kursawe R, D'Adamo E, Dykas DJ, Zhang CK, Bale AE, et al. A common variant in the patatin-like phospholipase 3 gene (PNPLA3) is associated with fatty liver disease in obese children and adolescents. Hepatology. 2010. 52:1281–1290.

12. McCullough AJ. Pathophysiology of nonalcoholic steatohepatitis. J Clin Gastroenterol. 2006. 40:S17–S29.

13. Angulo P. Nonalcoholic fatty liver disease. N Engl J Med. 2002. 346:1221–1231.

14. Ahima RS, Saper CB, Flier JS, Elmquist JK. Leptin regulation of neuroendocrine systems. Front Neuroendocrinol. 2000. 21:263–307.

15. Wellhoener P, Fruehwald-Schulters B, Kern W, Dantz D, Kerner W, Born J, et al. Glucose metabolism rather than insulin is a main determinant of leptin secretion in humans. J Clin Endocrinol Metab. 2000. 85:1267–1271.

16. Boden G, Chen X, Mozzoli M, Ryan I. Effect of fasting on serum leptin in normal human subjects. J Clin Endocrinol Metab. 1996. 81:3419–3423.

17. Farooqi IS, Matarese G, Lord GM, Keogh JM, Lawrence E, Agwu C, et al. Beneficial effects of leptin on obesity, T cell hyporesponsiveness, and neuroendocrine/metabolic dysfunction of human congenital leptin deficiency. J Clin Invest. 2002. 110:1093–1103.

18. Tartaglia LA, Dembski M, Weng X, Deng N, Culpepper J, Devos R, et al. Identification and expression cloning of a leptin receptor, OB-R. Cell. 1995. 83:1263–1271.

19. Corica F, Allegra A, Corsonello A, Buemi M, Calapai G, Ruello A, et al. Relationship between plasma leptin levels and the tumor necrosis factor-alpha system in obese subjects. Int J Obes Relat Metab Disord. 1999. 23:355–360.

20. Wang Z, Zhou YT, Kakuma T, Lee Y, Kalra SP, Kalra PS, et al. Leptin resistance of adipocytes in obesity: role of suppressors of cytokine signaling. Biochem Biophys Res Commun. 2000. 277:20–26.

21. Honda H, Ikejima K, Hirose M, Yoshikawa M, Lang T, Enomoto N, et al. Leptin is required for fibrogenic responses induced by thioacetamide in the murine liver. Hepatology. 2002. 36:12–21.

22. Hotamisligil GS, Shargill NS, Spiegelman BM. Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science. 1993. 259:87–91.

23. Hotamisligil GS, Peraldi P, Budavari A, Ellis R, White MF, Spiegelman BM. IRS-1-mediated inhibition of insulin receptor tyrosine kinase activity in TNF-alpha- and obesity-induced insulin resistance. Science. 1996. 271:665–668.

24. Panagiotakos DB, Pitsavos C, Yanakoulia M, Chrysohoou C, Stefanadis C. The implication of obesity and central fat on markers of chronic inflammation: The ATTICA study. Atherosclerosis. 2005. 183:308–315.

25. Tilg H, Moschen AR. Adipocytokines: mediators linking adipose tissue, inflammation and immunity. Nat Rev Immunol. 2006. 6:772–783.

26. Arita Y, Kihara S, Ouchi N, Takahashi M, Maeda K, Miyagawa J, et al. Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity. Biochem Biophys Res Commun. 1999. 257:79–83.

27. 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.

28. Papanicolaou DA, Vgontzas AN. Interleukin-6: the endocrine cytokine. J Clin Endocrinol Metab. 2000. 85:1331–1333.

29. Franckhauser S, Elias I, Rotter Sopasakis V, Ferré T, Nagaev I, Andersson CX, et al. Overexpression of Il6 leads to hyperinsulinaemia, liver inflammation and reduced body weight in mice. Diabetologia. 2008. 51:1306–1316.

30. Wieckowska A, Papouchado BG, Li Z, Lopez R, Zein NN, Feldstein AE. Increased hepatic and circulating interleukin-6 levels in human nonalcoholic steatohepatitis. Am J Gastroenterol. 2008. 103:1372–1379.

31. Rabe K, Lehrke M, Parhofer KG, Broedl UC. Adipokines and insulin resistance. Mol Med. 2008. 14:741–751.

32. Stejskal D, Adamovska S, Bartek J, Jurakova R, Proskova J. Resistin-concentrations in persons with type 2 diabetes mellitus and in individuals with acute inflammatory disease. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2003. 147:63–69.

33. Silha JV, Krsek M, Skrha JV, Sucharda P, Nyomba BL, Murphy LJ. Plasma resistin, adiponectin and leptin levels in lean and obese subjects: correlations with insulin resistance. Eur J Endocrinol. 2003. 149:331–335.

34. Singhal NS, Patel RT, Qi Y, Lee YS, Ahima RS. Loss of resistin ameliorates hyperlipidemia and hepatic steatosis in leptin-deficient mice. Am J Physiol Endocrinol Metab. 2008. 295:E331–E338.

35. Marra F, Bertolani C. Adipokines in liver diseases. Hepatology. 2009. 50:957–969.

36. Dong B, Saha PK, Huang W, Chen W, Abu-Elheiga LA, Wakil SJ, et al. Activation of nuclear receptor CAR ameliorates diabetes and fatty liver disease. Proc Natl Acad Sci USA. 2009. 106:18831–18836.

37. Zheng L, Lv GC, Sheng J, Yang YD. Effect of miRNA-10b in regulating cellular steatosis level by targeting PPAR-alpha expression, a novel mechanism for the pathogenesis of NAFLD. J Gastroenterol Hepatol. 2010. 25:156–163.

38. Sato R. SREBPs: protein interaction and SREBPs. FEBS J. 2009. 276:622–627.