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首页> 外文期刊>Cell and Tissue Research >Augmented expression of gamma-glutamyl transferase 5 (GGT5) impairs testicular steroidogenesis by deregulating local oxidative stress
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Augmented expression of gamma-glutamyl transferase 5 (GGT5) impairs testicular steroidogenesis by deregulating local oxidative stress

机译：γ-谷氨酰转移酶5（GGT5）的增强表达通过放松局部氧化应激来损害睾丸类固醇生成。

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An increasingly pro-oxidant environment has been widely implicated in causing dysfunction of testicular steroidogenesis, but little progress has been made in understanding the underlying molecular mechanism. Here, we report that gamma-glutamyl transferase 5 (GGT5), a key metabolism component responsible for the catalysis of important anti-oxidant glutathione (GSH), is predominantly expressed in mammalian Leydig cells (LCs). Deregulated GGT5 expression negatively correlates with testosterone deficiency in the testes of type 2 diabetic mice. Consistently, overexpression of GGT5 potentiates the susceptibility of TM3 LCs to spontaneous oxidative stress during luteinizing hormone (LH)-stimulated steroidogenesis. From a mechanistic standpoint, the deleterious effect of GGT5 overexpression on testicular steroidogenesis may stem from an alteration of the local redox state because of GSH deficiency. The above-mentioned response might involve the impairment of extracellular signal-related kinase activation mediated directly by oxidative injury or indirectly by abnormal P38 activation, which in turn inhibits steroidogenic acute regulatory protein abundance in mitochondria and thus significantly sabotages the rate-limiting step during LH-induced steroidogenesis. Alternatively, GGT5 overexpression induces heme oxygenase 1 (HO-1) expression, which, as a key catalyst responsible for the oxidative degradation of heme, may inhibit the activities of the cytochrome P450 monooxygenases, thus substantially impairing testicular steroidogenesis. These results, coupled with the differential roles of mitogen-activated protein kinases and HO-1 signaling in spermatogenesis, lead us to propose a model in which a delicate balance between these two pathways modulated by the GGT5/oxidative stress cascade plays a central role during LH-stimulated steroidogenesis.
机译：越来越多的促氧化剂环境已被广泛地引起睾丸类固醇生成功能障碍，但在理解潜在的分子机制方面进展甚微。在这里，我们报告，γ-谷氨酰转移酶5（GGT5），负责催化重要的抗氧化剂谷胱甘肽（GSH）的关键代谢成分，主要在哺乳动物Leydig细胞（LCs）中表达。在2型糖尿病小鼠的睾丸中，失调的GGT5表达与睾丸激素缺乏呈负相关。一致地，在促黄体生成激素（LH）刺激的类固醇生成过程中，GGT5的过表达增强了TM3 LC对自发氧化应激的敏感性。从机理的角度来看，由于GSH缺乏，GGT5过表达对睾丸类固醇生成的有害作用可能源于局部氧化还原状态的改变。上述反应可能涉及直接由氧化损伤或间接由异常P38激活介导的细胞外信号相关激酶激活的损伤，这继而抑制了线粒体中类固醇生成的急性调节蛋白的丰度，从而显着破坏了LH期间的限速步骤诱导的类固醇生成。或者，GGT5的过表达诱导血红素加氧酶1（HO-1）的表达，它作为负责血红素氧化降解的关键催化剂，可能抑制细胞色素P450单加氧酶的活性，从而大大损害睾丸类固醇的生成。这些结果，加上有丝分裂原激活的蛋白激酶和HO-1信号在精子发生中的不同作用，使我们提出了一个模型，其中由GGT5 /氧化应激级联调节的这两种途径之间的微妙平衡在此过程中起着核心作用。 LH刺激类固醇生成。

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