Advertisement

Obesity Surgery

, Volume 19, Issue 5, pp 617–624 | Cite as

Expression of Cytokine Signaling Genes in Morbidly Obese Patients with Non-Alcoholic Steatohepatitis and Hepatic Fibrosis

  • J. Michael Estep
  • Ancha Baranova
  • Noreen Hossain
  • Hazem Elariny
  • Kathy Ankrah
  • Arian Afendy
  • Vikas Chandhoke
  • Zobair M. Younossi
Research Article

Abstract

Background

White adipose tissue (WAT) from visceral adiposity plays an important role in the pathogenesis of non-alcoholic steatohepatitis (NASH). Development of NASH and its progression to fibrosis is partially due to cytokines and adipokines produced by WAT. The aim of this study was to assess the association of hepatic fibrosis and NASH by evaluating the intrinsic differences in the inflammatory cytokine signaling in the visceral adipose tissue obtained from morbidly obese patients.

Methods

We used targeted microarrays representing human genes involved in the inflammatory and fibrogenic reactions to profile visceral adipose samples of 15 well-matched NASH patients with and without fibrosis. Additionally, visceral adipose samples were subjected to real-time polymerase chain reaction profiling of 84 inflammations related genes.

Results

Eight genes (CCL2, CCL4, CCL18, CCR1, IL10RB, IL15RA, and LTB) were differentially expressed in NASH with fibrosis. Additionally, an overlapping but distinct list of the differentially expressed genes were found in NASH with type II diabetes (DM; IL8, BLR1, IL2RA, CD40LG, IL1RN, IL15RA, and CCL4) as compared to NASH without DM.

Conclusions

Inflammatory cytokines are differentially expressed in the adipose tissue of NASH with fibrosis, as well in NASH with DM. These findings point at the interaction of adipose inflammatory cytokines, DM, hepatic fibrosis in NASH, and its progression to cirrhosis and end-stage liver disease.

Keywords

NASH Fibrosis Morbid obesity 

Notes

Acknowledgments

This study was partly supported by the Liver Disease Outcomes Fund of the Center for Liver Diseases at Inova Fairfax Hospital and a Seed Grant from Inova Health System.

Financial Disclosure

None.

Supplementary material

11695_2009_9814_MOESM1_ESM.doc (170 kb)
Supplementary Table 1 List of human genes profiled in adipose samples of NASH patients by microarray. Genes that were present only in microarray experiment, but not in RT-PCR experiment, are in italic (DOC 174 kb)
11695_2009_9814_MOESM2_ESM.doc (132 kb)
Supplementary Table 2 List of human genes profiled in adipose samples of NASH patients by RT-PCR. Genes that were present only in RT PCR experiment, but not in microarray experiment, are in italic (DOC 134 kb)
11695_2009_9814_MOESM3_ESM.doc (106 kb)
Supplementary Table 3 Cytokine signaling-related (CSR) genes expressed in the adipose tissue in each of the patients’ cohorts (DOC 109 kb)

References

  1. 1.
    Machado M, Cortez-Pinto H. Non-alcoholic fatty liver disease and insulin resistance. Eur J Gastroenterol Hepatol. 2005;17:823–6.PubMedCrossRefGoogle Scholar
  2. 2.
    Ong J, Elariny H, Collantes R, et al. Predictors of nonalcoholic steatohepatitis and advanced fibrosis in obese patients. Obes Surg. 2005;15(3):310–15.PubMedCrossRefGoogle Scholar
  3. 3.
    Nugent C, Bai CH, Elariny H, et al. Improvement of metabolic syndrome after laparoscopic bariatric surgery. Obes Surg. 2008;18(10):1278–86.PubMedCrossRefGoogle Scholar
  4. 4.
    Baranova A, Gowder SJ, Schlauch K, et al. Gene expression of leptin, resistin, and adiponectin in the white adipose tissue of obese patients with non-alcoholic fatty liver disease and insulin resistance. Obes Surg. 2006;16:1118–25.PubMedCrossRefGoogle Scholar
  5. 5.
    Baranova A, Schlauch K, Elariny H, et al. Gene expression patterns in the hepatic tissue and in the visceral adipose tissue of patients with non-alcoholic fatty liver disease. Obes Surg. 2007;17(8):1111–8.PubMedCrossRefGoogle Scholar
  6. 6.
    Baranova A, Collantes R, Schlauch K, et al. A comparison of serum levels and gene expression of leptin, resistin and adiponectin in the adipose tissue of obese patients with non-alcoholic fatty liver disease and insulin resistance. Obes Surg. 2006;16(9):1118–25.PubMedCrossRefGoogle Scholar
  7. 7.
    Lee YH, Pratley RE. The evolving role of inflammation in obesity and the metabolic syndrome. Curr Diab Rep. 2005;5:70–5.PubMedCrossRefGoogle Scholar
  8. 8.
    Matteoni CA, Younossi ZM, Gramlich T, et al. Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity. Gastroenterology 1999;116:1413–9.PubMedCrossRefGoogle Scholar
  9. 9.
    Marchesini G, Brizi M, Bianchi G, et al. Nonalcoholic fatty liver disease. A feature of the metabolic syndrome. Diabetes 2001;50:1844–50.PubMedCrossRefGoogle Scholar
  10. 10.
    Gramlich T, Kleiner DE, McCullough AJ, et al. Pathologic features associated with fibrosis in non-alcoholic fatty liver disease. Human Pathol. 2004;35:196–99.CrossRefGoogle Scholar
  11. 11.
    Sasaki N, Ueno T, Morita Y, et al. Usefulness of serum hepatic fibrosis markers in the diagnosis of nonalcoholic steatohepatitis (NASH). Hepatogastroenterology 2006;53:678–81.PubMedGoogle Scholar
  12. 12.
    Hubscher SG. Histological assessment of non-alcoholic fatty liver disease. J Clin Gastroenterol. 2006;40:S5–10.Google Scholar
  13. 13.
    Weltman MD, Farrell GC, Liddle C. Increased hepatocyte CYP2E1 expression in a rat nutritional model of hepatic steatosis with inflammation. Gastroenterology 1996;111:1645–53.PubMedCrossRefGoogle Scholar
  14. 14.
    Geerts A. History, heterogeneity, developmental biology, and functions of quiescent hepatic stellate cells. Semin Liver Dis. 2001;21:3113–35.CrossRefGoogle Scholar
  15. 15.
    Fain JN. Release of interleukins and other inflammatory cytokines by human adipose tissue is enhanced in obesity and primarily due to the nonfat cells. Vitam Horm. 2006;74:443–77.PubMedCrossRefGoogle Scholar
  16. 16.
    You T, Nicklas BJ. Chronic inflammation: role of adipose tissue and modulation by weight loss. Curr Diabetes Rev. 2006;2:29–37.PubMedCrossRefGoogle Scholar
  17. 17.
    Jarrar MH, Baranova A, Collantes R, et al. Adipokines and cytokines in non-alcoholic fatty liver disease. Aliment Pharmacol Ther. 2008;27:412–21.PubMedCrossRefGoogle Scholar
  18. 18.
    Pradhan A. Obesity, metabolic syndrome, and type 2 diabetes: inflammatory basis of glucose. Nutr Rev. 2007;65:S152–56.PubMedCrossRefGoogle Scholar
  19. 19.
    Fain JN, Madan AK. Regulation of monocyte chemoattractant protein 1 (mcp-1) release by explants of human visceral adipose tissue. Int J Obes (Lond). 2005;29:1299–307.CrossRefGoogle Scholar
  20. 20.
    Sell H, Eckel J. Monocyte chemotactic protein-1 and its role in insulin resistance. Curr Opin Lipidol. 2007;18:258–62.PubMedCrossRefGoogle Scholar
  21. 21.
    Kanno K, Tazuma S, Nishioka T, et al. Angiotensin II participates in hepatic inflammation and fibrosis through MCP-1 expression. Dig Dis Sci. 2005;50:942–8.PubMedCrossRefGoogle Scholar
  22. 22.
    Zeyda M, Farmer D, Todoric J, et al. Human adipose tissue macrophages are of an anti-inflammatory phenotype but capable of excessive pro-inflammatory mediator production. Int J Obes (Lond). 2007;31:1420–28.CrossRefGoogle Scholar
  23. 23.
    Cipollone F, Chiarelli F, Davì G, et al. Enhanced soluble CD40 ligand contributes to endothelial cell dysfunction in vitro and monocyte activation in patients with diabetes mellitus: effect of improved metabolic control. Diabetologia 2005;48:1216–224.PubMedCrossRefGoogle Scholar
  24. 24.
    Afford SC, Ahmed-Choudhury J, Randhawa S, et al. CD40 activation-induced, Fas-dependent apoptosis and NF-kappaB/AP-1 signaling in human intrahepatic biliary epithelial cells. FASEB J. 2001;15:2345–54.PubMedCrossRefGoogle Scholar
  25. 25.
    Wieckowska A, Papouchado BG, Li Z, et al. Increased hepatic and circulating interleukin-6 levels in human nonalcoholic steatohepatitis. Am J Gastroenterol. 2008;103:1372–79.PubMedCrossRefGoogle Scholar
  26. 26.
    Fontana L, Eagon JC, Trujillo ME, et al. Visceral fat adipokine secretion is associated with systemic inflammation in obese humans. Diabetes 2007;56:1010–13.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science + Business Media, LLC 2009

Authors and Affiliations

  • J. Michael Estep
    • 1
    • 2
    • 3
  • Ancha Baranova
    • 1
    • 2
    • 3
  • Noreen Hossain
    • 3
  • Hazem Elariny
    • 3
  • Kathy Ankrah
    • 3
  • Arian Afendy
    • 1
    • 3
  • Vikas Chandhoke
    • 2
    • 3
  • Zobair M. Younossi
    • 1
    • 2
    • 3
  1. 1.Center for Liver DiseasesInova Fairfax HospitalFalls ChurchUSA
  2. 2.Center for the Study of Genomics in Liver Diseases, Molecular and Microbiology DepartmentGeorge Mason UniversityFairfaxUSA
  3. 3.Translational Research InstituteInova Health SystemFalls ChurchUSA

Personalised recommendations