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首页> 外文学位 >Adipocyte protein carbonylation and oxidative stress in obesity-linked mitochondrial dysfunction and insulin resistance.
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Adipocyte protein carbonylation and oxidative stress in obesity-linked mitochondrial dysfunction and insulin resistance.

机译：肥胖相关的线粒体功能障碍和胰岛素抵抗的脂肪细胞蛋白羰基化和氧化应激。

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摘要

Carbonylation is the covalent, non-reversible modification of the side chains of cysteine, histidine and lysine residues by lipid peroxidation end products such as 4-hydroxy- and 4-oxononenal. The antioxidant enzyme glutathione S-transferase A4 (GSTA4) catalyzes a major detoxification pathway for such reactive lipids but its expression was selectively down regulated in the obese, insulin resistant adipocyte resulting in increased protein carbonylation. The effects of such modifications are associated with increased oxidative stress and metabolic dysregulation centered on mitochondrial energy metabolism. Mitochondrial functions in adipocytes of lean or obese GSTA4 null mice were significantly compromised compared to wild type controls and were accompanied by an increase in superoxide anion. Silencing GSTA4 mRNA in cultured adipocytes resulted in increased protein carbonylation, increased mitochondrial ROS, dysfunctional state 3 respiration and altered glucose transport and lipolysis.;To address the role of protein carbonylation in the pathogenesis of mitochondrial dysfunction quantitative proteomics was employed to identify specific targets of carbonylation in GSTA4-silenced or overexpressing 3T3-L1 adipocytes. GSTA4-silenced adipocytes displayed elevated carbonylation of several key mitochondrial proteins including the phosphate carrier protein, NADH dehydrogenase 1 alpha subcomplexes 2 and 3, translocase of inner mitochondrial membrane 50, and valyl-tRNA synthetase. Elevated protein carbonylation is accompanied by diminished complex I activity, impaired respiration, increased superoxide production and a reduction in membrane potential without changes in mitochondrial number, area or density. These results suggest protein carbonylation plays a major instigating role in mitochondrial dysfunction and may be a linked to the development of insulin resistance in the adipocyte.
机译：羰基化是半胱氨酸，组氨酸和赖氨酸残基的侧链通过脂质过氧化终产物（例如4-羟基和4-氧酮）的共价不可逆修饰。抗氧化剂酶谷胱甘肽S-转移酶A4（GSTA4）催化此类反应性脂质的主要排毒途径，但其表达在肥胖的胰岛素抵抗性脂肪细胞中选择性下调，导致蛋白质羰基化增加。这种修饰的作用与增加的氧化应激和以线粒体能量代谢为中心的代谢失调有关。与野生型对照相比，瘦或肥胖的GSTA4缺失小鼠的脂肪细胞中的线粒体功能显着受损，并伴有超氧阴离子的增加。沉默培养的脂肪细胞中的GSTA4 mRNA会导致蛋白质羰基化增加，线粒体ROS升高，状态3呼吸功能障碍以及葡萄糖转运和脂解作用改变。 GSTA4沉默或过表达的3T3-L1脂肪细胞中的羰基化作用。 GSTA4沉默的脂肪细胞显示出几个关键的线粒体蛋白的羰基化升高，包括磷酸盐载体蛋白，NADH脱氢酶1α亚复合物2和3，线粒体内膜50的转位酶和valyl-tRNA合成酶。蛋白质羰基化升高伴随着复杂的I活性降低，呼吸功能受损，超氧化物生成增加以及膜电位降低，而线粒体数，面积或密度没有变化。这些结果表明蛋白质羰基化在线粒体功能障碍中起主要的诱使作用，并且可能与脂肪细胞中胰岛素抵抗的发展有关。

著录项

  • 作者

    Curtis, Jessica Marie.;

  • 作者单位

    University of Minnesota.;

  • 授予单位 University of Minnesota.;
  • 学科 Chemistry Biochemistry.
  • 学位 Ph.D.
  • 年度 2011
  • 页码 174 p.
  • 总页数 174
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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