Increased hepatic myeloperoxidase activity in obese subjects with nonalcoholic steatohepatitis.
Inflammation and oxidative stress are considered critical factors in the progression of nonalcoholic fatty liver disease. Myeloperoxidase (MPO) is an important neutrophil enzyme that can generate aggressive oxidants; therefore, we studied the association between MPO and nonalcoholic fatty liver disease. The distribution of inflammatory cells containing MPO in liver biopsies of 40 severely obese subjects with either nonalcoholic steatohepatitis (NASH) (n = 22) or simple steatosis (n = 18) was investigated by immunohistochemistry. MPO-derived oxidative protein modifications were identified by immunohistochemistry and correlated to hepatic gene expression of CXC chemokines and M1/M2 macrophage markers as determined by quantitative PCR. MPO plasma levels were determined by ELISA. The number of hepatic neutrophils and MPO-positive Kupffer cells was increased in NASH and was accompanied by accumulation of hypochlorite-modified and nitrated proteins, which can be generated by the MPO-H2O2 system. Liver CXC chemokine expression was higher in patients with accumulation of MPO-mediated oxidation products and correlated with hepatic neutrophil sequestration. Plasma MPO levels were elevated in NASH patients. Interestingly, neutrophils frequently surrounded steatotic hepatocytes, resembling the crown-like structures found in obese adipose tissue. Furthermore, hepatic M2 macrophage marker gene expression was increased in NASH. Our data indicate that accumulation of MPO-mediated oxidation products, partly derived from Kupffer cell MPO, is associated with induction of CXC chemokines and hepatic neutrophil infiltration and may contribute to the development of NASH.
Rensen
Sander S
SS
Department of Surgery, Maastricht University Medical Centre, PO Box 616, Maastricht 6200 MD, The Netherlands. s.rensen@ah.unimaas.nl
Slaats
Yanti
Y
Nijhuis
Jeroen
J
Jans
Anneke
A
Bieghs
Veerle
V
Driessen
Ann
A
Malle
Ernst
E
Greve
Jan Willem
JW
Buurman
Wim A
WA
D000328:Adult; D000438:Alcohols; D015415:Biomarkers / Q000378:metabolism; D002452:Cell Count; D019743:Chemokines, CXC / Q000378:metabolism; D005234:Fatty Liver / Q000097:blood / Q000150:complications* / Q000201:enzymology*; D005260:Female; D006801:Humans; D006997:Hypochlorous Acid / Q000378:metabolism; D007728:Kupffer Cells / Q000201:enzymology / Q000473:pathology; D008099:Liver / Q000201:enzymology* / Q000473:pathology*; D008297:Male; D009504:Neutrophils / Q000378:metabolism; D009566:Nitrates / Q000378:metabolism; D009765:Obesity / Q000097:blood / Q000150:complications* / Q000201:enzymology*; D009195:Peroxidase / Q000097:blood / Q000378:metabolism*; D010641:Phenotype
D000438:Alcohols; D015415:Biomarkers; D019743:Chemokines, CXC; D009566:Nitrates; D006997:Hypochlorous Acid; D009195:Peroxidase