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

PLoS One. 2012;7(12):e52411. doi: 10.1371/journal.pone.0052411. Epub 2012 Dec 20.


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 ~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-α 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipose Tissue / metabolism
  • Adipose Tissue / pathology
  • Animals
  • Cholesterol / metabolism
  • Diet, High-Fat
  • Enzyme Induction
  • Fatty Liver / complications
  • Fatty Liver / enzymology*
  • Fatty Liver / pathology*
  • Feeding Behavior
  • Humans
  • Inflammation / metabolism
  • Inflammation / pathology
  • Liver / enzymology
  • Liver / pathology
  • Liver Cirrhosis / complications
  • Liver Cirrhosis / metabolism
  • Liver Cirrhosis / pathology
  • Mice
  • Mice, Inbred C57BL
  • Neutrophils / enzymology*
  • Non-alcoholic Fatty Liver Disease
  • Peroxidase / biosynthesis
  • Peroxidase / metabolism*
  • Receptors, LDL / deficiency*
  • Receptors, LDL / metabolism
  • Triglycerides / metabolism


  • Receptors, LDL
  • Triglycerides
  • Cholesterol
  • Peroxidase

Grants and funding

Supported by the Senter Novem Innovation Oriented Research Program on Genomics, grant IGE05012 (MH/JWG/WB), a Transnational University Limburg grant and a Dutch Digestive Foundation project grant (WO 09-46) to SR, and VENI grant 916.76.070 from the Netherlands Organization for Scientific Research (RS). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.