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Uric acid and anti‐TNF antibody improve mitochondrial dysfunction in ob/ob mice
Author(s) -
GarcíaRuiz Inmaculada,
RodríguezJuan Cristina,
DíazSanjuan Teresa,
del Hoyo Pilar,
Colina Francisco,
MuñozYagüe Teresa,
SolísHerruzo José A.
Publication year - 2006
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.21313
Subject(s) - peroxynitrite , chemistry , endocrinology , medicine , nitrotyrosine , tyrosine , tumor necrosis factor alpha , uric acid , nitric oxide synthase , microbiology and biotechnology , nitric oxide , biochemistry , biology , enzyme , superoxide
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 β‐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. (H EPATOLOGY 2006;44:581–591.)