Glucose availability is a decisive factor for Nrf2-mediated gene expression.
Glucose availability is a decisive factor for Nrf2-mediated gene expression.
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DOI：
10.1016/j.redox.2013.06.001
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发表时间：
2013
期刊：
影响因子：
11.4
通讯作者：
Dirsch, Verena M.
中科院分区：
文献类型：
--
作者：
Heiss, Elke H.;Schachner, Daniel;Zimmermann, Kristin;Dirsch, Verena M.
转录因子Nrf2(核因子-红系2相关因子2)的激活是抵抗氧化应激和异物应激的主要细胞防线之一，但也影响与脂肪和糖代谢有关的基因。Nrf2介导的细胞保护和代谢反应在非恶性细胞中是连接的还是分离的，目前还没有定论。在这项研究中，我们发现，无论是通过小分子萝卜硫素还是敲除Nrf2抑制剂Keap1来激活Nrf2，都会导致细胞对葡萄糖的摄取增加，并增加成纤维细胞对葡萄糖的依赖。当Nrf2被激活时，葡萄糖优先通过戊糖磷酸途径代谢，NADPH的产量增加。干扰葡萄糖或戊糖磷酸途径的供应和NADPH的产生不仅在酶水平上阻碍Nrf2介导的活性氧物种的解毒，而且还阻碍Nrf2启动的抗氧化防御蛋白的表达，如谷胱甘肽还原酶和血红素加氧酶1。我们的结论是，Nrf2依赖的对氧化应激的保护依赖于完整的戊糖磷酸途径，并且在哺乳动物细胞的基因表达水平上，代谢和解毒之间已经存在串扰。Nrf2的激活导致细胞葡萄糖摄取增加。当Nrf2被激活时，葡萄糖优先通过PPP代谢。由此导致的NADPH的增加不仅对ROS的功能解毒至关重要，而且对哺乳动物细胞中依赖Nrf2的基因表达也是至关重要的。这些数据补充了我们对Nrf2作用的代谢阴影的理解。
Activation of the transcription factor Nrf2 (nuclear factor-erythroid 2-related factor 2) is one of the major cellular defense lines against oxidative and xenobiotic stress, but also influences genes involved in lipid and glucose metabolism. It is unresolved whether the cytoprotective and metabolic responses mediated by Nrf2 are connected or separable events in non-malignant cells. In this study we show that activation of Nrf2, either by the small molecule sulforaphane or knockout of the Nrf2 inhibitor Keap1, leads to increased cellular glucose uptake and increased glucose addiction in fibroblasts. Upon Nrf2 activation glucose is preferentially metabolized through the pentose phosphate pathway with increased production of NADPH. Interference with the supply of glucose or the pentose phosphate pathway and NADPH generation not only hampers Nrf2-mediated detoxification of reactive oxygen species on the enzyme level but also Nrf2-initiated expression of antioxidant defense proteins, such as glutathione reductase and heme-oxygenase1. We conclude that the Nrf2-dependent protection against oxidative stress relies on an intact pentose phosphate pathway and that there is crosstalk between metabolism and detoxification already at the level of gene expression in mammalian cells. Activation of Nrf2 results in increased cellular glucose uptake. Upon activation of Nrf2 glucose is preferentially metabolized through the PPP. The resulting increase in NADPH is not only pivotal for functional detoxification of ROS, but also for Nrf2-dependent gene expression in mammalian cells. These data complement our understanding of the metabolic shade of Nrf2 action.
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影响因子：
5
作者：
Shin, Soona;Wakabayashi, Junko;Yates, Melinda S.;Wakabayashi, Nobunao;Dolan, Patrick M.;Aja, Susan;Liby, Karen T.;Sporn, Michael B.;Yamamoto, Masayuki;Kensler, Thomas W.
通讯作者：
Kensler, Thomas W.
DOI：
10.1124/jpet.109.162271
发表时间：
2010-04-01
影响因子：
3.5
作者：
Aleksunes, Lauren M.;Reisman, Scott A.;Klaassen, Curtis D.
通讯作者：
Klaassen, Curtis D.
影响因子：
5.3
作者：
Shin, Soona;Wakabayashi, Nobunao;Kensler, Thomas W.
通讯作者：
Kensler, Thomas W.
影响因子：
4.7
作者：
Yates, Melinda S.;Tran, Quynh T.;Kensler, Thomas W.
通讯作者：
Kensler, Thomas W.
影响因子：
5.3
作者：
Uruno, Akira;Furusawa, Yuki;Yamamoto, Masayuki
通讯作者：
Yamamoto, Masayuki