萝卜硫素重新连接中枢代谢以支持抗氧化反应并实现葡萄糖稳态,Redox Biology

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萝卜硫素重新连接中枢代谢以支持抗氧化反应并实现葡萄糖稳态
Redox Biology ( IF 10.7 ) Pub Date : 2023-09-07 , DOI: 10.1016/j.redox.2023.102878
Federico Bernuzzi ₁ , Andre Maertens ₂ , Shikha Saha ₁ , Perla Troncoso-Rey ₁ , Tobias Ludwig ₂ , Karsten Hiller ₂ , Richard F Mithen ₃ , Tamas Korcsmaros ₄ , Maria H Traka ₁

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富含十字花科植物的饮食，尤其是西兰花，可以降低患各种部位的癌症、心血管疾病和 2 型糖尿病的风险。萝卜硫素 (SF) 是一种含硫的西兰花衍生代谢物，已被确定为介导这些健康益处的主要生物活性化合物。萝卜硫素是转录因子类红细胞核因子 2 (NRF2) 的有效饮食激活剂，NRF2 是抗氧化细胞能力的主要调节剂，负责诱导细胞保护基因，但其在葡萄糖稳态中的作用仍不清楚。在这项研究中，我们准备测试以下假设：SF 通过在人肝癌 HepG2 细胞中诱导 NRF2 来调节葡萄糖代谢并改善葡萄糖超载及其产生的氧化应激。HepG2 细胞暴露于不同的葡萄糖浓度：基础葡萄糖 (5.5 mM) 和高葡萄糖 (25 mM)，以及生理浓度的 SF (10 μM)。SF 上调谷胱甘肽 (GSH) 生物合成基因的表达，并显着提高还原型 GSH 的水平。测量代谢通量的标记葡萄糖和谷氨酰胺实验发现，SF 通过将甘氨酸和谷氨酸从 TCA 循环中重新定向来增加细胞内对甘氨酸和谷氨酸的利用，并增加从培养基中导入的半胱氨酸，可能支持谷胱甘肽的合成。此外，SF改变了产生NADPH（氧化还原酶反应必需的辅助因子）的途径，即磷酸戊糖途径和1C代谢，导致葡萄糖从糖酵解转向PPP，以及甲硫氨酸转向甲基化底物。最后，对使用 CRISPR-Cas9 基因组编辑生成的 NRF2-KD HepG2 细胞进行转录组学和靶向代谢组学 LC-MS 分析，结果表明上述代谢效应是通过 NRF2 介导的。这些结果表明十字花科植物饮食的抗氧化特性与其代谢益处密切相关。

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Sulforaphane rewires central metabolism to support antioxidant response and achieve glucose homeostasis

Cruciferous-rich diets, particularly broccoli, have been associated with reduced risk of developing cancers of various sites, cardiovascular disease and type-2 diabetes. Sulforaphane (SF), a sulfur-containing broccoli-derived metabolite, has been identified as the major bioactive compound mediating these health benefits. Sulforaphane is a potent dietary activator of the transcription factor Nuclear factor erythroid-like 2 (NRF2), the master regulator of antioxidant cell capacity responsible for inducing cytoprotective genes, but its role in glucose homeostasis remains unclear. In this study, we set to test the hypothesis that SF regulates glucose metabolism and ameliorates glucose overload and its resulting oxidative stress by inducing NRF2 in human hepatoma HepG2 cells. HepG2 cells were exposed to varying glucose concentrations: basal (5.5 mM) and high glucose (25 mM), in the presence of physiological concentrations of SF (10 μM). SF upregulated the expression of glutathione (GSH) biosynthetic genes and significantly increased levels of reduced GSH. Labelled glucose and glutamine experiments to measure metabolic fluxes identified that SF increased intracellular utilisation of glycine and glutamate by redirecting the latter away from the TCA cycle and increased the import of cysteine from the media, likely to support glutathione synthesis. Furthermore, SF altered pathways generating NADPH, the necessary cofactor for oxidoreductase reactions, namely pentose phosphate pathway and 1C-metabolism, leading to the redirection of glucose away from glycolysis and towards PPP and of methionine towards methylation substrates. Finally, transcriptomic and targeted metabolomics LC-MS analysis of NRF2-KD HepG2 cells generated using CRISPR-Cas9 genome editing revealed that the above metabolic effects are mediated through NRF2. These results suggest that the antioxidant properties of cruciferous diets are intricately connected to their metabolic benefits.

更新日期：2023-09-07

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