Original Article | Published:

Pediatrics

Heme oxygenase-1 gene promoter polymorphism and the risk of pediatric nonalcoholic fatty liver disease

International Journal of Obesity volume 39, pages 12361240 (2015) | Download Citation

Abstract

Background and objectives:

Oxidative stress and the insulin-resistant state are thought to be key components in the pathogenesis of pediatric nonalcoholic fatty liver disease (NAFLD). Heme oxygenase (HO) is important in the defense against oxidative stress. This study aimed to assess the association of HO-1 gene promoter polymorphism and insulin resistance with NAFLD among obese children.

Methods:

A total of 101 obese children aged 6–17 years were recruited. Anthropometric, serum biochemical variables and biomarkers for glucose and insulin metabolism were measured. We screened the allelic frequencies of (GT)n repeats in the HO-1 gene promoter among these obese children. NAFLD was determined through liver ultrasonography. Because the distribution of numbers of (GT)n repeats was bimodal, we divided the alleles into two classes: class S included shorter (27) repeats, and class L included longer (27) repeats. We assessed the effects of the length of (GT)n repeats in HO-1 gene promoter on pediatric NAFLD.

Results:

Of the 101 obese subjects, 27 (26.7%) had NAFLD. The alanine aminotransferase level was higher in patients carrying L alleles (L/L and L/S) than patients with S alleles (S/S) (46.2±49.3 IU|−1 versus 30.2±20.1 IU|−1; P=0.027). The significant risk factors for pediatric NAFLD were patients carrying L alleles (L/L and L/S) (odds ratio (OR)=18.84; 95% confidence interval (CI): 1.45–245.22; P=0.025), homeostasis model assessment of insulin resistance (OR=1.40; 95% CI: 1.07–1.83; P=0.014) and age (OR=1.24; 95% CI: 1.03–1.50; P=0.025).

Conclusion:

In this hospital-based study, the obese children with longer GT repeats in the HO-1 gene promoter and insulin resistance were susceptible to NAFLD.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    , , , , , et al. Comparison of overweight and obesity prevalence in school-aged youth from 34 countries and their relationships with physical activity and dietary patterns. Obes Rev 2005; 6: 123–132.

  2. 2.

    , , , , , . Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity. Gastroenterology 1999; 116: 1413–1419.

  3. 3.

    , , , , . Variants in the UGT1A1 gene and the risk of pediatric non-alcoholic fatty liver disease. Pediatrics 2009; 124: 1221–1227.

  4. 4.

    , , , , , . A common variant in the PNPLA3 gene is a risk factor of non-alcoholic fatty liver disease in Taiwanese obese children. J Pediatr 2011; 158: 740–744.

  5. 5.

    , , , . A common variant in the peroxisome proliferator-activated receptor-γ coactivator-1α gene is associated with nonalcoholic fatty liver disease in obese children. Am J Clin Nutr 2013; 97: 326–331.

  6. 6.

    , , , . Genetic variants in GCKR and PNPLA3 confer susceptibility to nonalcoholic fatty liver disease in obese individuals. Am J Clin Nutr 2014; 99: 869–874.

  7. 7.

    , , . Nonalcoholic steatohepatitis. J Gastroenterol Hepatol 1997; 12: 398–403.

  8. 8.

    , , , , , et al. Non alcoholic steatohepatitis: association of insulin resistance and mitochondrial abnormalities. Gastroenterology 2001; 120: 1183–1192.

  9. 9.

    , , , , , et al. Highly liver-specific heme oxygenase-1 induction by interleukin-11 prevents carbon tetrachlorideinduced hepatotoxicity. Int J Mol Med 2006; 18: 537–546.

  10. 10.

    , , , , , et al. rAAV-mediated stable expression of heme oxygenase-1 in stellate cells: a new approach to attenuate liver fibrosis in rats. Hepatology 2005; 42: 335–342.

  11. 11.

    , , , , , et al. Heme oxygenase- 1a fundamental guardian against oxidative tissue injuries in acute inflammation. Mini Rev Med Chem 2007; 7: 745–753.

  12. 12.

    , , . Heme oxygenase-1/carbon monoxide: from basic science to therapeutic applications. Physiol Rev 2006; 86: 583–650.

  13. 13.

    , , , , , . Protective functions of heme oxygenase-1 and carbon monoxide in the respiratory system. Antioxid Redox Signal 2007; 9: 2157–2173.

  14. 14.

    , , . Carbon monoxide and bilirubin: potential therapies for pulmonary/vascular injury and disease. Am J Respir Cell Mol Biol 2007; 36: 175–182.

  15. 15.

    , , , , . Identification of binding sites for transcription factors NF-B and AP-2 in the promoter region of the human heme oxygenase-1 gene. Proc Natl Acad Sci USA 1994; 91: 5987–5991.

  16. 16.

    , , , , , et al. Microsatellite polymorphism in the heme oxygenase-1 gene promoter is associated with susceptibility to emphysema. Am J Hum Genet 2000; 66: 187–195.

  17. 17.

    , , , , , et al. Microsatellite polymorphism in promoter of heme oxygenase-1 gene is associated with susceptibility to coronary artery disease in type 2 diabetic patients. Hum Genet 2002; 111: 1–8.

  18. 18.

    , , , , , et al. Heme oxygenase-1 gene promoter polymorphism is associated with coronary artery disease in Japanese patients with coronary risk factors. Arterioscler Thromb Vasc Biol 2002; 22: 1680–1685.

  19. 19.

    , , , , , et al. Nonalcoholic steatohepatitis, insulin resistance, and metabolic syndrome: further evidence for an etiologic association. Hepatology 2002; 35: 367–372.

  20. 20.

    , . New growth charts for Taiwanese children and adolescents based on World Health Organization standards and health-related physical fitness. Pediatr Neonatol 2010; 51: 69–79.

  21. 21.

    , , , , , et al. NASH and insulin resistance: insulin hypersecretion and specific association with the insulin resistance syndrome. Hepatology 2002; 35: 373–379.

  22. 22.

    , , , , , . Metabolic syndrome and liver histology in paediatric non-alcoholic steatohepatitis. Int J Obes 2008; 32: 381–387.

  23. 23.

    , , , , , et al. Non-alcoholic fatty liver disease: An early mediator predicting metabolic syndrome in obese children? World J Gastroenterol 2011; 17: 735–742.

  24. 24.

    , , , , , et al. Hepatic steatosis in obese Chinese children. Int J Obes Relat Metab Disord 2004; 28: 1257–1263.

  25. 25.

    , , , , , et al. Diagnostic accuracy and reliability of ultrasonography for the detection of fatty liver: a meta-analysis. Hepatology 2011; 54: 1082–1090.

  26. 26.

    , . d(TG)n.d(CA)n sequences upstream of the rat prolactin gene from Z-DNA and inhibit gene transcription. Nucleic Acids Res 1990; 18: 1595–1601.

  27. 27.

    , , , , , et al. Increased HO-1 levels ameliorate fatty liver development through a reduction of heme and recruitment of FGF21. Obesity 2014; 22: 705–712.

  28. 28.

    , . Heme-oxygenase-1 as a potential therapeutic target for hepatoprotection. J Biochem Mol Biol 2006; 39: 479–491.

  29. 29.

    , . Heme oxygenase-1 (HO-1), a protective gene that prevents chronic graft dysfunction. Free Radic Biol Med 2005; 38: 426–435.

  30. 30.

    , , , , , et al. Protection of transplant-induced renal ischemia-reperfusion injury with carbon monoxide. Am J Physiol Renal Physiol 2004; 287: F979–789.

  31. 31.

    , , , . Genes of the antioxidant response undergo upregulation in a rodent model of nonalcoholic steatohepatitis. J Biochem Mol Toxicol 2007; 21: 216–220.

  32. 32.

    , , , , , et al. Heme oxygenase-1 protects against steatohepatitis in both cultured hepatocytes and mice. Gastroenterology 2010; 138: 694–704.

  33. 33.

    , . Review: The role of insulin resistance in nonalcoholic fatty liver disease. J Clin Endocrinol Metab 2006; 91: 4753–4761.

  34. 34.

    , , , , , et al. Nonalcoholic fatty liver disease: A feature of the metabolic syndrome. Diabetes 2001; 50: 1844–1850.

  35. 35.

    , , , , , et al. Insulin resistance in non-diabetic patients with non-alcoholic fatty liver disease: Sites and mechanisms. Diabetologia 2005; 48: 634–642.

  36. 36.

    , , , , , et al. Fat accumulation in the liver is associated with defects in insulin suppression of glucose production and serum free fatty acids independent of obesity in normal men. J Clin Endocrinol Metab 2002; 87: 3023–3028.

  37. 37.

    , , , . Prevalence and trends in obesity among US adults, 1999–2000. JAMA 2002; 288: 1723–1727.

  38. 38.

    , , , , . Idiopathic steatohepatitis in childhood: A multicenter retrospective study. J Pediatr 1995; 127: 700–704.

  39. 39.

    , , , . Central role of suppressors of cytokine signaling proteins in hepatic steatosis, insulin resistance, and the metabolic syndrome in the mouse. Proc Natl Acad Sci USA 2004; 101: 10422–10427.

Download references

Acknowledgements

We are indebted to Jyh-Feng Lu for laboratory work, and to Chien-Hao Chen for assistance with the statistical analysis. This work was supported by research grants from the Far Eastern Memorial Hospital (FEMH- 2011- C - 30 and FEMH- 2012- C- 040).

Author information

Affiliations

  1. Department of Pediatrics, Far Eastern Memorial Hospital, Pan-Chiao, New Taipei, Taiwan

    • P-F Chang
    • , Y-C Lin
    • , K Liu
    •  & S-J Yeh
  2. Department of Healthcare Administration, Oriental Institute of Technology, Pan-Chiao, New Taipei, Taiwan

    • P-F Chang
    • , Y-C Lin
    •  & S-J Yeh
  3. Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan

    • Y-H Ni

Authors

  1. Search for P-F Chang in:

  2. Search for Y-C Lin in:

  3. Search for K Liu in:

  4. Search for S-J Yeh in:

  5. Search for Y-H Ni in:

Competing interests

The authors declare no conflict of interest.

Corresponding author

Correspondence to Y-H Ni.

About this article

Publication history

Received

Revised

Accepted

Published

DOI

https://doi.org/10.1038/ijo.2015.46