Downregulation of adipose glutathione S-transferase A4 leads to increased protein carbonylation, oxidative stress, and mitochondrial dysfunction.
Downregulation of adipose glutathione S-transferase A4 leads to increased protein carbonylation, oxidative stress, and mitochondrial dysfunction.
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DOI：
10.2337/db09-1105
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发表时间：
2010-05
期刊：
影响因子：
7.7
通讯作者：
Bernlohr DA
中科院分区：
文献类型：
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作者：
Curtis JM;Grimsrud PA;Wright WS;Xu X;Foncea RE;Graham DW;Brestoff JR;Wiczer BM;Ilkayeva O;Cianflone K;Muoio DE;Arriaga EA;Bernlohr DA
外周胰岛素抵抗与活性氧物种(ROS)的增加有关，部分导致活性脂醛的产生，在称为蛋白质羰化的反应中改变蛋白质氨基酸的侧链。脂醛脱毒的主要酶促方法是谷胱甘肽S转移酶A4依赖的谷胱甘肽。本研究旨在探讨GSTA4在脂肪细胞中的表达及其在脂肪细胞功能中的作用(S)。对GSTA4沉默的3T3-L1脂肪细胞和GSTA4缺失小鼠的代谢过程、线粒体功能和活性氧产生进行了评估。应用基因芯片技术检测GSTA4在肥胖人群中的表达。GSTA4在肥胖胰岛素抵抗C57BL/6J小鼠和人类肥胖相关胰岛素抵抗小鼠的脂肪组织中表达选择性下调。肿瘤坏死因子-α处理的3T3-L1脂肪细胞降低了GSTA4的表达，沉默培养的脂肪细胞GSTA4mRNA导致蛋白质羰化增加，线粒体ROS增加，呼吸功能障碍的状态3，并改变葡萄糖运输和脂解。与野生型对照相比，瘦小或肥胖的GSTA4缺失小鼠脂肪细胞的线粒体功能显著受损，并伴随着超氧阴离子的增加。这些结果表明，脂肪组织中GSTA4的下调导致蛋白质羰化、ROS产生和线粒体功能障碍的增加，并可能参与胰岛素抵抗和2型糖尿病的发展。
Peripheral insulin resistance is linked to an increase in reactive oxygen species (ROS), leading in part to the production of reactive lipid aldehydes that modify the side chains of protein amino acids in a reaction termed protein carbonylation. The primary enzymatic method for lipid aldehyde detoxification is via glutathione S-transferase A4 (GSTA4) dependent glutathionylation. The objective of this study was to evaluate the expression of GSTA4 and the role(s) of protein carbonylation in adipocyte function. GSTA4-silenced 3T3-L1 adipocytes and GSTA4-null mice were evaluated for metabolic processes, mitochondrial function, and reactive oxygen species production. GSTA4 expression in human obesity was evaluated using microarray analysis. GSTA4 expression is selectively downregulated in adipose tissue of obese insulin-resistant C57BL/6J mice and in human obesity-linked insulin resistance. Tumor necrosis factor-α treatment of 3T3-L1 adipocytes decreased GSTA4 expression, and silencing GSTA4 mRNA in cultured adipocytes resulted in increased protein carbonylation, increased mitochondrial ROS, dysfunctional state 3 respiration, and altered glucose transport and lipolysis. Mitochondrial function in adipocytes of lean or obese GSTA4-null mice was significantly compromised compared with wild-type controls and was accompanied by an increase in superoxide anion. These results indicate that downregulation of GSTA4 in adipose tissue leads to increased protein carbonylation, ROS production, and mitochondrial dysfunction and may contribute to the development of insulin resistance and type 2 diabetes.