Uric acid and anti-TNF antibody improve mitochondrial dysfunction in ob/ob mice.
The mechanisms responsible for low mitochondrial respiratory chain (MRC) activity in the liver of patients with nonalcoholic steatohepatitis are unknown. In this study, we examined the cause of this dysfunction in ob/ob mice. Forty-six mice were distributed in six groups: group I: C57BL/6J mice; group II: C57BL/6J Lep(-/-) mice (ob/ob); group III, ob/ob mice treated with manganese [III] tetrakis (5,10,15,20 benzoic acid) porphyrin (MnTBAP); group IV, ob/ob mice treated with IgG1 immunoglobulin; group V, ob/ob mice treated with anti-TNF antibody; group VI: ob/ob mice treated with uric acid. In liver tissue, we measured MRC activity, fatty acid beta-oxidation, tumor necrosis factor (TNF), inducible nitric oxide synthase (iNOS), 3-tyrosine-nitrated proteins, 3-tyrosine-nitrated mitochondrial proteins, including cytochrome c and ND4 subunit of complex I. MRC activity was decreased in ob/ob mice. TNF levels, iNOS protein expression, and tyrosine nitrated proteins were markedly increased in the liver of ob/ob mice. In these animals, mitochondrial proteins were markedly tyrosine nitrated, particularly the ND4 subunit of complex I and cytochrome c. Treatment of these animals with uric acid, a peroxynitrite scavenger, anti-TNF antibody, or MnTBAP decreased tyrosine nitrated proteins, improved the activity of MRC complexes, and led to a marked regression of hepatic steatosis and inflammation. In conclusion, MRC dysfunction and liver lesions found in ob/ob mice are likely to reflect the tyrosine nitration of mitochondrial proteins by peroxynitrite or a peroxynitrite-derivate radical. Increased hepatic TNF and iNOS expression might enhance peroxynitrite formation and inhibition of MRC complexes.
García-Ruiz
Inmaculada
I
Research Center, Department of Gastroenterology, Hospital Universitario 12 de Octubre, Avd. Córdoba, Madrid, Spain.
Rodríguez-Juan
Cristina
C
Díaz-Sanjuan
Teresa
T
del Hoyo
Pilar
P
Colina
Francisco
F
Muñoz-Yagüe
Teresa
T
Solís-Herruzo
José A
JA
D000818:Animals; D000906:Antibodies / Q000627:therapeutic use*; D015153:Blotting, Western; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005234:Fatty Liver / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D005434:Flow Cytometry; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology; D007371:Interferon-gamma / Q000378:metabolism; D007375:Interleukin-1 / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism*; D028361:Mitochondrial Diseases / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology*; D014527:Uric Acid / Q000627:therapeutic use*
D000906:Antibodies; D007375:Interleukin-1; D014409:Tumor Necrosis Factor-alpha; D014527:Uric Acid; D007371:Interferon-gamma; D052247:Nitric Oxide Synthase Type II