Skip to main content

Advertisement

SpringerLink
Log in

Influence of adiponectin gene polymorphisms in Japanese patients with non-alcoholic fatty liver disease

  • Original Article—Liver, Pancreas, and Biliary Tract
  • Published:
Journal of Gastroenterology Aims and scope Submit manuscript

Abstract

Purpose

Single nucleotide polymorphisms (SNPs) of the adiponectin gene have been reported to be associated with insulin resistance and the prevalence of type-2 diabetes. We investigated the SNPs of adiponectin in non-alcoholic fatty liver disease (NAFLD) patients.

Methods

One hundred nineteen patients histologically diagnosed as having NAFLD and 115 control subjects were examined. Adiponectin SNP sites were investigated at +45 of exon 2 and at +276 of intron 2; these sites have been thought to be associated with diabetes or insulin resistance.

Results

Regarding the +276 SNP, the frequency of G/G tended to be higher in NAFLD patients than in controls, but not significantly. Among females only, however, the G/G frequency was significantly higher in NAFLD patients. As for the +45 SNP, in the severe fibrosis group, the frequency of G/G homozygotes was significantly higher than that in the mild fibrosis group, and G/G homozygotes of the +45 SNP proved by multivariate analysis to be an independent factor in severe fibrosis. In NAFLD patients with adiponectin +45 G/G, homeostasis model assessment-insulin resistance was significantly higher than in NAFLD patients without adiponectin +45 G/G.

Conclusion

Adiponectin SNPs were found to be associated with the progression of liver fibrosis and insulin resistance, suggesting that adiponectin SNPs might play roles in the occurrence and progression of NAFLD.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Teli MR, James OFW, Burt AD, Bennet MK, Day CP. The natural history of nonalcoholic fatty liver: follow-up study. Hepatology. 1995;22:1714–9.

    Article  PubMed  CAS  Google Scholar 

  2. Neuschwander-Tetri BA, Caldwell SH. Nonalcoholic steatohepatitis; summary of an AASLD single topic conference. Hepatology. 2003;37:1202–19.

    Article  PubMed  Google Scholar 

  3. 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 

  4. Stefan N, Kantartzis K, Häring HU. Causes and metabolic consequences of fatty liver. Endocr Rev. 2008;29:939–60.

    Article  PubMed  CAS  Google Scholar 

  5. Wigg AJ, Roberts-Thomson IC, Dymock RB, McCarthy PJ, Crose RH, Cummins AG. The role of small intestinal bacterial overgrowth, intestinal permeability, endotoxaemia, and tumor necrosis factor alpha in pathogenesis of non-alcoholic steatohepatitis. Gut. 2001;48:148–9.

    Article  Google Scholar 

  6. Starkel P, Sempoux C, Leclercq I, Herin M, Deby C, Desager JP, et al. Oxidative stress, KLF6 and transforming growth factor-beta up-regulation differentiate non-alcoholic steatohepatitis progressing to fibrosis from uncomplicated steatosis in rats. J Hepatol. 2003;39:538–46.

    Article  PubMed  Google Scholar 

  7. Hara K, Yamauchi T, Kadowaki T. Adiponectin: an adipokine linking adipocytes and type 2 diabetes in humans. Curr Diabetes Rep. 2005;5:136–40.

    Article  CAS  Google Scholar 

  8. Hotta K, Funahashi T, Arita Y, Takahashi M, Matsuda M, Okamoto Y, et al. Plasma concentrations of a novel, adipose-specific protein, adiponectin, in type 2 diabetic patients. Arterioscler Thromb Vasc Biol. 2000;20:1595–9.

    PubMed  CAS  Google Scholar 

  9. Hui JM, Hodge A, Farrell GC, Kench JG, Kriketos A, George J. Beyond insulin resistance in NASH: TNF-alpha or adiponectin? Hepatology. 2004;40:46–54.

    Article  PubMed  CAS  Google Scholar 

  10. Shimada M, Kawahara H, Ozaki K, Fukura M, Yano H, Tsuchishima M, et al. Usefulness of a combined evaluation of the serum adiponectin level, HOMA-IR, and serum type IV collagen 7S level to predict the early stage of nonalcoholic steatohepatitis. Am J Gastroenterol. 2007;102:1931–8.

    Article  PubMed  CAS  Google Scholar 

  11. Ma H, Gomez V, Lu L, Yang X, Wu X, Xiao SY. Expression of adiponectin and its receptors in livers of morbidly obese patients with non-alcoholic fatty liver disease. J Gastroenterol Hepatol. 2009;24:233–7.

    Article  PubMed  CAS  Google Scholar 

  12. Kamada Y, Tamura S, Kiso S, Matsumoto H, Saji Y, Yoshida Y, et al. Enhanced carbon tetrachloride-induced liver fibrosis in mice lacking adiponectin. Gastroenterology. 2003;125:1796–807.

    Article  PubMed  CAS  Google Scholar 

  13. Matsumoto H, Tamura S, Kamada Y, Kiso S, Fukushima J, Wada A, et al. Adiponectin deficiency exacerbates lipopolysaccharide/d-galactosamine-induced liver injury in mice. World J Gastroenterol. 2007;12:3352–8.

    Google Scholar 

  14. Picot F, Briant L, Jongeneel CV, Molvig J, Worsaae H, Abbal M, et al. Association of tumor necrosis (TNF) and class II major histocompatibility alleles with TNF alpha and TNF beta by human mononuclear cells; a possible link to insulin dependent diabetes mellitus. Eur J Immunol. 1993;23:224–31.

    Article  Google Scholar 

  15. Tokushige K, Takakura M, Tsuchiya-Matsushita N, Taniai M, Hashimoto E, Shiratori K. Influence of TNF gene polymorphisms in Japanese patients with NASH and simple steatosis. J Hepatol. 2007;46:1104–10.

    Article  PubMed  CAS  Google Scholar 

  16. Hara K, Boutin P, Mori Y, Tobe K, Dina C, Yasuda K, et al. Genetic variation in the gene encoding adiponectin is associated with an increased risk of type 2 diabetes in the Japanese population. Diabetes. 2002;51:536–40.

    Article  PubMed  CAS  Google Scholar 

  17. Warodomwichit D, Shen J, Arnett DK, Tsai MY, Kabagambe EK, Peacock JM, et al. ADIPOQ polymorphisms, monounsaturated fatty acids, and obesity risk: The GOLDN Study. Obesity. 2009;17:510–7.

    Article  PubMed  CAS  Google Scholar 

  18. Goyenechea E, Collins LJ, Parra D, Abete I, Crujeiras AB, O’Dell SD, et al. The -11391 G/A polymorphism of the adiponectin gene promoter is associated with metabolic syndrome traits and the outcome of an energy-restricted diet in obese subjects. Horm Metab Res. 2009;41:55–61.

    Article  PubMed  CAS  Google Scholar 

  19. Huang H, Tada-Iida K, Murakami H, Saito Y, Otsuki T, Iemitsu M, et al. Influence of adiponectin gene polymorphism SNP276 (G/T) on adiponectin in response to exercise training. Endocr J. 2007;54:879–86.

    Article  PubMed  CAS  Google Scholar 

  20. Jang Y, Lee JH, Chae JS, Kim OY, Koh SJ, Kim JY, et al. Association of the 276G->T polymorphism of the adiponectin gene with cardiovascular disease risk factors in nondiabetic Koreans. Am J Clin Nutr. 2005;82:760–7.

    PubMed  CAS  Google Scholar 

  21. Zhang N, Shi YH, Hao CF, Gu HF, Li Y, Zhao YR, et al. Association of +45G15G(T/G) and +276(G/T) polymorphisms in the ADIPOQ gene with polycystic ovary syndrome among Han Chinese women. Eur J Endocrinol. 2008;158:255–60.

    Article  PubMed  CAS  Google Scholar 

  22. Kleiner DE, Brunt EM, Natta MV, Behling C, Contos MJ, Cummings OW, et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology. 2005;41:1313–21.

    Article  PubMed  Google Scholar 

  23. 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. Diabetalogia. 1985;28:412–9.

    Article  CAS  Google Scholar 

  24. 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;94:2467–74.

    Article  PubMed  CAS  Google Scholar 

  25. Brunt EM. Nonalcoholic steatohepatitis: definition and pathology. Semin Liver Dis. 2001;21:3–16.

    Article  PubMed  CAS  Google Scholar 

  26. Yoshioka K, Yoshida T, Umekawa T, Kogure A, Takakura Y, Toda H, et al. Adiponectin gene polymorphism (G276T) is not associated with incipient diabetic nephropathy in Japanese type 2 diabetic patients. Metabolism. 2004;53:1223–6.

    Article  PubMed  CAS  Google Scholar 

  27. Farrell GC, Larter CZ. Nonalcoholic fatty liver disease: from steatosis to cirrhosis. Hepatology. 2006;43:S99–112.

    Article  PubMed  CAS  Google Scholar 

  28. Musso G, Gambino R, Durazzo M, Biroli G, Carello M, Fagà E, et al. Adipokines in NASH: postprandial lipid metabolism as a link between adiponectin and liver disease. Hepatology. 2005;42:1175–83.

    Article  PubMed  CAS  Google Scholar 

  29. 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;40:1461–5.

    Article  PubMed  CAS  Google Scholar 

  30. Tokushige K, Hashimoto E, Kabutake A, Shiratori K. Questionnaire survey of lifestyle in the patients with nonalcoholic steatohepatitis. Jpn J Gastroenterol. 2006;103:A934.

    Google Scholar 

  31. Jang Y, Chae JS, Koh SJ, Hyun YJ, Kim JY, Jeong YJ, et al. The influence of the adiponectin gene on adiponectin concentrations and parameters of metabolic syndrome in non-diabetic Korean women. Clin Chim Acta. 2008;391:85–90.

    Article  PubMed  CAS  Google Scholar 

  32. Haap M, Machicao F, Stefan N, Thamer C, Tschritter O, Schnuck F, et al. Genetic determinants of insulin action in polycystic ovary syndrome. Exp Clin Endocrinol Diabetes. 2005;113:275–81.

    Article  PubMed  CAS  Google Scholar 

  33. Xita N, Georgiou I, Chatzikyriakidou A, Vounatsou M, Papassotiriou GP, Papassotiriou I, et al. Effect of adiponectin gene polymorphisms on circulating adiponectin and insulin resistance indexes in women with polycystic ovary syndrome. Clin Chem. 2005;51:416–23.

    Article  PubMed  CAS  Google Scholar 

  34. Musso G, Gambino R, De Michieli F, Durazzo M, Pagano G, Cassader M. Adiponectin gene polymorphisms modulate acute adiponectin response to dietary fat: possible pathogenetic role in NASH. Hepatology. 2008;47:1167–77.

    Article  PubMed  CAS  Google Scholar 

  35. González-Sánchez JL, Martínez-Calatrava MJ, Martínez-Larrad MT, Zabena C, Fernández-Pérez C, Laakso M, et al. Interaction of the -308G/A promoter polymorphism of the tumor necrosis factor-alpha gene with single-nucleotide polymorphism 45 of the adiponectin gene: effect on serum adiponectin concentrations in a Spanish population. Clin Chem. 2006;52:97–103.

    Article  PubMed  Google Scholar 

  36. Browning JD, Szczepaniak LS, Dobbins R, Nuremberg P, Horton JD, Cohen JC, et al. Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity. Hepatology. 2004;40:1387–95.

    Article  PubMed  Google Scholar 

  37. Valenti L, Fracanzani AL, Dongiovanni P, Santorelli G, Branchi A, Taioli E, et al. Tumor necrosis factor alpha promoter polymorphisms and insulin resistance in nonalcoholic fatty liver disease. Gastroenterology. 2002;122:274–80.

    Article  PubMed  CAS  Google Scholar 

  38. Shimada M, Hashimoto E, Kaneda H, Noguchi S, Hayashi N. Nonalcoholic steatohepatitis: risk factors for liver fibrosis. Hepatol Res. 2002;24:429–38.

    Article  PubMed  Google Scholar 

  39. Stefan N, Machicao F, Staiger H, Machann J, Schick F, Tschritter O, et al. Polymorphisms in the gene encoding adiponectin receptor 1 are associated with insulin resistance and high liver fat. Diabetologia. 2005;48:2282–91.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Medicine and Gastroenterology, Tokyo Women’s Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo, 162-8666, Japan

    Katsutoshi Tokushige, Etsuko Hashimoto, Haruka Noto, Satoru Yatsuji, Makiko Taniai, Nobuyuki Torii & Keiko Shiratori

Authors
  1. Katsutoshi Tokushige
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Etsuko Hashimoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Haruka Noto
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Satoru Yatsuji
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Makiko Taniai
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Nobuyuki Torii
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Keiko Shiratori
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Katsutoshi Tokushige.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Tokushige, K., Hashimoto, E., Noto, H. et al. Influence of adiponectin gene polymorphisms in Japanese patients with non-alcoholic fatty liver disease. J Gastroenterol 44, 976–982 (2009). https://doi.org/10.1007/s00535-009-0085-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00535-009-0085-z

Keywords

Search

Navigation