转录因子Nrf2(核因子-红细胞2相关因子2)的激活是抵抗氧化和外源性应激的主要细胞防御线之一,但也影响与脂质和葡萄糖代谢有关的基因。在非恶性细胞中,Nrf2介导的细胞保护和代谢反应是相关的还是可分离的,目前尚未解决。在这项研究中,我们表明Nrf2的激活,无论是通过小分子萝卜硫烷还是Nrf2抑制剂Keap1的敲除,都会导致成纤维细胞中细胞葡萄糖摄取增加和葡萄糖成瘾增加。在Nrf2活化后,随着NADPH的产生增加,葡萄糖优先通过磷酸戊糖途径代谢。干扰葡萄糖的供应或磷酸戊糖途径和NADPH的产生不仅会阻碍Nrf2介导的活性氧在酶水平上的解毒,而且还会阻碍Nrf2引发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。我们得出的结论是,Nrf2依赖性的抗氧化应激保护作用依赖于完整的磷酸戊糖途径,并且在哺乳动物细胞中的基因表达水平上,代谢和解毒之间已经存在串扰。
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.