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首页> 美国卫生研究院文献>Proceedings of the National Academy of Sciences of the United States of America >Decline in transcriptional activity of Nrf2 causes age-related loss of glutathione synthesis which is reversible with lipoic acid
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Decline in transcriptional activity of Nrf2 causes age-related loss of glutathione synthesis which is reversible with lipoic acid

机译：Nrf2转录活性的下降会导致与年龄相关的谷胱甘肽合成损失这是硫辛酸可逆的

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Glutathione (GSH) significantly declines in the aging rat liver. Because GSH levels are partly a reflection of its synthetic capacity, we measured the levels and activity of γ-glutamylcysteine ligase (GCL), the rate-controlling enzyme in GSH synthesis. With age, both the catalytic (GCLC) and modulatory (GCLM) subunits of GCL decreased by 47% and 52%, respectively (P < 0.005). Concomitant with lower subunit levels, GCL activity also declined by 53% (P < 0.05). Because nuclear factor erythroid2-related factor 2 (Nrf2) governs basal and inducible GCLC and GCLM expression by means of the antioxidant response element (ARE), we hypothesized that aging results in dysregulation of Nrf2-mediated GCL expression. We observed an ≈50% age-related loss in total (P < 0.001) and nuclear (P < 0.0001) Nrf2 levels, which suggests attenuation in Nrf2-dependent gene transcription. By using gel-shift and supershift assays, a marked reduction in Nrf2/ARE binding in old vs. young rats was noted. To determine whether the constitutive loss of Nrf2 transcriptional activity also affects the inducible nature of Nrf2 nuclear translocation, old rats were treated with (R)-α-lipoic acid (LA; 40 mg/kg i.p. up to 48 h), a disulfide compound shown to induce Nrf2 activation in vitro and improve GSH levels in vivo. LA administration increased nuclear Nrf2 levels in old rats after 12 h. LA also induced Nrf2 binding to the ARE, and, consequently, higher GCLC levels and GCL activity were observed 24 h after LA injection. Thus, the age-related loss in GSH synthesis may be caused by dysregulation of ARE-mediated gene expression, but chemoprotective agents, like LA, can attenuate this loss.
机译：谷胱甘肽（GSH）在衰老的大鼠肝脏中显着下降。由于GSH的水平部分反映了其合成能力，因此我们测量了GSH合成中的速率控制酶γ-谷氨酰半胱氨酸连接酶（GCL）的水平和活性。随着年龄的增长，GCL的催化亚基（GCLC）和调节性亚基（GCLM）分别下降了47％和52％（P <0.005）。伴随亚基水平降低，GCL活性也下降了53％（P <0.05）。由于核因子红系相关因子2（Nrf2）通过抗氧化剂响应元件（ARE）调控基础和诱导型GCLC和GCLM表达，因此我们假设衰老会导致Nrf2介导的GCL表达失调。我们观察到总的（P <0.001）和核的（P <0.0001）Nrf2水平下降了约50％，这表明Nrf2依赖性基因转录减弱。通过使用凝胶位移和超位移测定法，发现老年鼠和幼鼠的Nrf2 / ARE结合明显减少。为了确定Nrf2转录活性的组成性丧失是否也影响Nrf2核易位的诱导性质，用（R）-α-硫辛酸（LA; 40 mg / kg ip长达48 h），一种二硫化物处理了老年大鼠。证明在体外诱导Nrf2活化并在体内提高GSH水平。 12小时后，LA给药增加了老年大鼠的核Nrf2水平。 LA还诱导Nrf2与ARE结合，因此在LA注射后24小时观察到更高的GCLC水平和GCL活性。因此，GSH合成中与年龄有关的损失可能是由ARE介导的基因表达失调引起的，但是化学保护剂（如LA）可以减轻这种损失。

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