Neutrophil-derived myeloperoxidase aggravates non-alcoholic steatohepatitis in low-density lipoprotein receptor-deficient mice

S.S.M. Rensen, V. Bieghs, S.A. Xanthoulea, E. Arfianti, J.A. Bakker, R. Shiri-Sverdlov, M.H. Hofker, J.W. Greve, W.A. Buurman

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Abstract

BACKGROUND: Chronic inflammation and oxidative stress play fundamental roles in the pathogenesis of non-alcoholic steatohepatitis (NASH). Previously, we reported that myeloperoxidase (MPO), an aggressive oxidant-generating neutrophil enzyme, is associated with NASH severity in man. We now investigated the hypothesis that MPO contributes to the development and progression of NASH. METHODOLOGY: Low-density lipoprotein receptor-deficient mice with an MPO-deficient hematopoietic system (LDLR(-/-/)MPO(-/-tp) mice) were generated and compared with LDLR(-/-/)MPO(+/+tp) mice after induction of NASH by high-fat feeding. RESULTS: High-fat feeding caused a approximately 4-fold induction of liver MPO in LDLR(-/-/)MPO(+/+) mice which was associated with hepatic sequestration of MPO-positive neutrophils and high levels of nitrotyrosine, a marker of MPO activity. Importantly, LDLR(-/-/)MPO(-/-tp) mice displayed markedly reduced hepatic neutrophil and T-lymphocyte infiltration (p<0.05), and strong down regulation of pro-inflammatory genes such as TNF-alpha and IL-6 (p<0.05, p<0.01) in comparison with LDLR(-/-/)MPO(+/+tp) mice. Next to the generalized reduction of inflammation, liver cholesterol accumulation was significantly diminished in LDLR(-/-/)MPO(-/-tp) mice (p = 0.01). Moreover, MPO deficiency appeared to attenuate the development of hepatic fibrosis as evident from reduced hydroxyproline levels (p<0.01). Interestingly, visceral adipose tissue inflammation was markedly reduced in LDLR(-/-/)MPO(-/-tp) mice, with a complete lack of macrophage crown-like structures. In conclusion, MPO deficiency attenuates the development of NASH and diminishes adipose tissue inflammation in response to a high fat diet, supporting an important role for neutrophils in the pathogenesis of metabolic disease.
Original languageEnglish
Article number52411
Number of pages10
JournalPLOS ONE
Volume7
Issue number12
DOIs
Publication statusPublished - 20 Dec 2012

Keywords

  • FATTY LIVER-DISEASE
  • INSULIN-RESISTANCE
  • HYPOCHLOROUS ACID
  • OXIDATIVE STRESS
  • ATHEROSCLEROTIC LESIONS
  • SCAVENGER RECEPTORS
  • ACTIVATION
  • INFLAMMATION
  • MATRIX
  • IMPACT

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