T2DM-elicited oxidative stress represses MTA3 expression in mouse Leydig cells.
T2DM-elicited oxidative stress represses MTA3 expression in mouse Leydig cells.
复制标题
T2DM引起的氧化应激抑制小鼠Leydig细胞中的MTA3表达。
DOI：
10.1530/rep-21-0413
复制
发表时间：
2022-03
期刊：
影响因子：
3.8
通讯作者：
Fei Liu;Zhen-Zhen Chen-Zhen;Jie Zhao;Yuan-qiang Zhang;Jing Ma;Wei Li
中科院分区：
文献类型：
--
作者：
Fei Liu;Zhen-Zhen Chen-Zhen;Jie Zhao;Yuan-qiang Zhang;Jing Ma;Wei Li
转移相关蛋白3（MTA3）在癌症和生理环境中作为多功能的辅助调节因子发挥作用。最近出现了MTA3在间质间质细胞（LC）中的主要表达及其作为睾丸类固醇生成的局部调节剂的作用。胰岛素孵育降低LCs中MTA3表达的浓度和暴露时间依赖性的方式。这提出了胰岛素在直接控制MTA3表达中的额外内分泌作用的可能性，这迄今为止尚未探索。在此，我们报道了2型糖尿病（T2DM）介导的MTA3抑制与睾丸氧化应激增加有关。相反，强抗氧化剂褪黑激素的灌胃有效地改善了氧化应激，恢复了MTA 3的表达，但未能改变睾酮缺乏（TD）的糖尿病小鼠的血清胰岛素水平。使用多种生物化学方法，我们证明了氧化应激通过抑制核受体亚家族4 A组成员1（NR4A1）介导的小鼠LC中Mta3的反式激活来抑制MTA3的表达。相反，NR4A1的异位表达改善了LC中氧化应激受损的MTA 3表达。通过采用一种有效的体内基因转移方法，显微注射慢病毒质粒，我们表明，补充MTA 3的表达在体内部分恢复睾丸类固醇生成和改善男性生育能力的糖尿病小鼠TD。因此，我们揭示了一个中央调控枢纽，涉及氧化应激受损NR4A1驱动的转录激活的MTA 3在刺激的LC，作为一个潜在的机制，调节高胰岛素血症和男性不育症与TD之间的串扰。
Metastasis-associated protein 3 (MTA3) functions as a versatile coregulator in cancers and in physiological contexts. A predominant expression of MTA3 in interstitial Leydig cells (LCs) and its role as a local modulator of testicular steroidogenesis have recently emerged. Incubation with insulin decreased MTA3 expression in a concentration- and exposure time-dependent manner in LCs. This raises the possibility of additional endocrine actions of insulin in the direct control of MTA3 expression, which remains so far unexplored. Herein, we reported that type 2 diabetes mellitus (T2DM)-mediated inhibition of MTA3 was associated with an increase in testicular oxidative stress. In contrast, a gavage of the strong antioxidant melatonin effectively ameliorated oxidative stress and restored the expression of MTA3, but failed to change serum insulin levels in the diabetic mice with testosterone deficiency (TD). Using multiple biochemical approaches, we demonstrated that oxidative stress suppressed MTA3 expression via repression of nuclear receptor subfamily 4 group A member 1 (NR4A1)-mediated transactivation of Mta3 in mouse LCs. By contrast, ectopic expression of NR4A1 ameliorated oxidative stress-impaired MTA3 expression in LCs. By employing an effective in vivo gene transfer method with microinjection of lentiviral plasmids, we showed that replenishment of MTA3 expression in vivo partially restored testicular steroidogenesis and improved male fertility in diabetic mice with TD. Thus, we have unveiled a central regulatory hub, involving oxidative stress-impaired NR4A1-driven transactivation of MTA3 in stimulated LCs, as a potential mechanism regulating crosstalk between hyperinsulinemia and male infertility associated with TD.