title: Neutrophil-derived myeloperoxidase aggravates non-alcoholic steatohepatitis in low-density lipoprotein receptor-deficient mice.
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.
  
  
  METHODS
  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.
authors.affiliation: Department of Surgery, NUTRIM School for Nutrition, Toxicology and Metabolism, Maastricht University Medical Centre, Maastricht, The Netherlands. s.rensen@maastrichtuniversity.nl
authors.forename: Sander S
authors.initials: SS
authors.lastname: Rensen
authors.forename: Veerle
authors.initials: V
authors.lastname: Bieghs
authors.forename: Sofia
authors.initials: S
authors.lastname: Xanthoulea
authors.forename: Evi
authors.initials: E
authors.lastname: Arfianti
authors.forename: Jaap A
authors.initials: JA
authors.lastname: Bakker
authors.forename: Ronit
authors.initials: R
authors.lastname: Shiri-Sverdlov
authors.forename: Marten H
authors.initials: MH
authors.lastname: Hofker
authors.forename: Jan Willem
authors.initials: JW
authors.lastname: Greve
authors.forename: Wim A
authors.initials: WA
authors.lastname: Buurman
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism / Q000473:pathology; D000818:Animals; D002784:Cholesterol / Q000378:metabolism; D059305:Diet, High-Fat; D004790:Enzyme Induction; D005234:Fatty Liver / Q000150:complications / Q000201:enzymology* / Q000473:pathology*; D005247:Feeding Behavior; D006801:Humans; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000201:enzymology / Q000473:pathology; D008103:Liver Cirrhosis / Q000150:complications / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000201:enzymology*; D065626:Non-alcoholic Fatty Liver Disease; D009195:Peroxidase / Q000096:biosynthesis / Q000378:metabolism*; D011973:Receptors, LDL / Q000172:deficiency* / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism
chemical_list: D011973:Receptors, LDL; D014280:Triglycerides; D002784:Cholesterol; D009195:Peroxidase