Decreased nucleotide excision repair in steatotic livers associates with myeloperoxidase-immunoreactivity.

M.A.C. Schults, P.W. Nagle, S.S.M. Rensen, R.W.L. Godschalk, A. Munnia, M. Peluso, S. M. Claessen, J.W. Greve, A.L.C. Driessen, F.J. Verdam, W.A. Buurman, F.J. van Schooten, R.K. Chiu

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6 Citations (Scopus)

Abstract

Chronic inflammation is characterized by the influx of neutrophils and is associated with an increased production of reactive oxygen species that can damage DNA. Oxidative DNA damage is generally thought to be involved in the increased risk of cancer in inflamed tissues. We previously demonstrated that activated neutrophil mediated oxidative stress results in a reduction in nucleotide excision repair (NER) capacity, which could further enhance mutagenesis. Inflammation and oxidative stress are critical factors in the progression of nonalcoholic fatty liver disease that is linked with enhanced liver cancer risk. In this report, we therefore evaluated the role of neutrophils and the associated oxidative stress in damage recognition and DNA repair in steatotic livers of 35 severely obese subjects with either nonalcoholic steatohepatitis (NASH) (n=17) or steatosis alone (n=18). The neutrophilic influx in liver was assessed by myeloperoxidase (MPO) staining and the amount of oxidative DNA damage by measuring M(1)dG adducts. No differences in M(1)dG adduct levels were observed between patients with or without NASH and also not between individuals with high or low MPO immunoreactivity. However, we found that high expression of MPO in the liver, irrespective of disease status, reduced the damage recognition capacity as determined by staining for histone 2AX phosphorylation (gammaH2AX). This reduction in gammaH2AX formation in individuals with high MPO immunoreactivity was paralleled by a significant decrease in NER capacity as assessed by a functional repair assay, and was not related to cell proliferation. Thus, the observed reduction in NER capacity upon hepatic inflammation is associated with and may be a consequence of reduced damage recognition. These findings suggest a novel mechanism of liver cancer development in patients with nonalcoholic fatty liver disease.
Original languageEnglish
Pages (from-to)75-81
Number of pages7
JournalMutation Research-Fundamental and Molecular Mechanisms of Mutagenesis
Volume736
Issue number1-2
DOIs
Publication statusPublished - 1 Aug 2012

Keywords

  • Nucleotide excision repair
  • Myeloperoxidase
  • Nonalcoholic steatohepatitis
  • Chronic inflammation
  • Oxidative stress
  • PULMONARY EPITHELIAL-CELLS
  • OXIDATIVE DNA-DAMAGE
  • NONALCOHOLIC STEATOHEPATITIS
  • HEPATOCELLULAR-CARCINOMA
  • MOLECULAR-MECHANISMS
  • H2AX PHOSPHORYLATION
  • LIPID-PEROXIDATION
  • NATURAL-HISTORY
  • INSULIN-RESISTANCE
  • LUNG-CANCER

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