Uric acid and anti-TNF antibody improve mitochondrial dysfunction in ob/ob mice
Uric acid and anti-TNF antibody improve mitochondrial dysfunction in ob/ob mice
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DOI：
10.1002/hep.21313
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发表时间：
2006-09-01
期刊：
影响因子：
13.5
通讯作者：
Solis-Herruzo, Jose A.
中科院分区：
文献类型：
--
作者：
Garcia-Ruiz, Inmaculada;Rodriguez-Juan, Cristina;Solis-Herruzo, Jose A.
非酒精性脂肪性肝炎患者肝脏线粒体呼吸链（MRC）活性低的机制尚不清楚。在这项研究中，我们检查了ob/ob小鼠这种功能障碍的原因。46只小鼠分为6组：第一组：C57BL/6J小鼠；II组：C57BL/6J Lep（-/-）小鼠（ob/ob）；III组，用锰[III]四（5,10,15,20苯甲酸）卟啉（MnTB-AP）处理ob/ob小鼠；IV组，IgG1免疫球蛋白处理的ob/ob小鼠；V组：抗tnf抗体处理的ob/ob小鼠，VI组：尿酸处理的ob/ob小鼠。在肝组织中，我们测量了MRC活性、脂肪酸p氧化、肿瘤坏死因子（TNF）、诱导型一氧化氮合酶（iNOS）、3-酪氨酸硝化蛋白、3-酪氨酸硝化线粒体蛋白，包括细胞色素c和复合物i的ND4亚基。ob/ob小鼠肝脏中TNF水平、iNOS蛋白表达和酪氨酸硝化蛋白显著升高。在这些动物中，线粒体蛋白明显被酪氨酸硝化，特别是复合物I的ND4亚基和细胞色素c。用尿酸、过氧亚硝酸盐清除剂、抗tnf抗体或mnttap治疗这些动物，可以减少酪氨酸硝化蛋白，提高MRC复合物的活性，并导致肝脂肪变性和炎症的显著消退。总之，在ob/ob小鼠中发现的MRC功能障碍和肝脏病变可能反映了过氧亚硝酸盐或过氧亚硝酸盐衍生物自由基对线粒体蛋白的酪氨酸硝化作用。肝脏TNF和iNOS表达的增加可能会促进过氧亚硝酸盐的形成和抑制MRC复合物。
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 (MnTB-AP); group IV, ob/ob mice treated with IgG1 immunoglobutin; 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 P-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.