Research Summary: 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.


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.

____________________________

Publisher: Public Library of Science

Date Published: 20-December-2012

Author(s): Rensen S., Bieghs V., Xanthoulea S., Arfianti E., Bakker J., Shiri-Sverdlov R., Hofker M., Greve J., Buurman W.

Link: https://doi.org/10.1371/journal.pone.0052411

Leave a Reply

Your email address will not be published. Required fields are marked *