Sulforaphane rewires central metabolism to support antioxidant response and achieve glucose homeostasis.
Sulforaphane rewires central metabolism to support antioxidant response and achieve glucose homeostasis.
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DOI：
10.1016/j.redox.2023.102878
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发表时间：
2023-11
期刊：
影响因子：
11.4
通讯作者：
Traka, Maria H.
中科院分区：
文献类型：
--
作者：
Bernuzzi, Federico;Maertens, Andre;Saha, Shikha;Troncoso-Rey, Perla;Ludwig, Tobias;Hiller, Karsten;Mithen, Richard F.;Korcsmaros, Tamas;Traka, Maria H.
关键词：
富含十字花科植物的饮食，特别是西兰花，与降低患各种部位癌症、心血管疾病和2型糖尿病的风险有关。萝卜硫素（SF），一种含硫的西兰花衍生代谢产物，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核因子红细胞样2（NRF 2）的有效膳食激活剂，NRF 2是负责诱导细胞保护基因的抗氧化细胞能力的主要调节因子，但其在葡萄糖稳态中的作用仍不清楚。在这项研究中，我们设置为测试的假设，SF调节葡萄糖代谢和改善葡萄糖超载及其产生的氧化应激诱导NRF 2在人肝癌HepG 2细胞。在生理浓度的SF（10 μM）存在下，将HepG 2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）。SF上调谷胱甘肽（GSH）生物合成基因的表达，并显着增加还原型GSH的水平。标记的葡萄糖和谷氨酰胺的实验，以测量代谢通量确定，SF增加甘氨酸和谷氨酸的细胞内利用，通过重定向后者远离TCA循环，并增加半胱氨酸从媒体的进口，可能支持谷胱甘肽的合成。此外，SF改变了产生NADPH（氧化还原酶反应的必要辅因子）的途径，即戊糖磷酸途径和1C代谢，导致葡萄糖从糖酵解转向PPP，蛋氨酸转向甲基化底物。最后，使用CRISPR-Cas9基因组编辑产生的NRF 2-KD HepG 2细胞的转录组学和靶向代谢组学LC-MS分析显示，上述代谢作用是通过NRF 2介导的。这些结果表明，十字花科饮食的抗氧化特性与其代谢益处密切相关。高葡萄糖阻断还原型谷胱甘肽的产生，而SF逆转了这种作用。为了支持谷胱甘肽的生物合成，SF导致甘氨酸、半胱氨酸和谷氨酸的消耗。在高葡萄糖SF改变NADPH产生途径（戊糖磷酸途径和1C代谢），以满足谷胱甘肽的需求。CRISPR-Cas 9揭示了SF诱导的代谢效应由NRF 2介导。
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. High glucose blocks reduced glutathione production, whilst SF reverses the effects. To support glutathione biosynthesis, SF results in glycine, cysteine and glutamate consumption. In high glucose SF alters NADPH-producing pathways (Pentose Phosphate Pathway and 1C-metabolism) to meet glutathione demand. CRISPR-Cas 9 reveals that the metabolic effects induced by SF are mediated by NRF2.
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影响因子：
14.9
作者：
Chorley BN;Campbell MR;Wang X;Karaca M;Sambandan D;Bangura F;Xue P;Pi J;Kleeberger SR;Bell DA
通讯作者：
Bell DA
影响因子：
11.4
作者：
Heiss, Elke H.;Schachner, Daniel;Zimmermann, Kristin;Dirsch, Verena M.
通讯作者：
Dirsch, Verena M.
影响因子：
10.5
作者：
Itoh, K;Wakabayashi, N;Yamamoto, M
通讯作者：
Yamamoto, M
影响因子：
5.3
作者：
Kobayashi, Makoto;Li, Li;Yamamoto, Masayuki
通讯作者：
Yamamoto, Masayuki
影响因子：
17.1
作者：
Axelsson, Annika S.;Tubbs, Emily;Rosengren, Anders H.
通讯作者：
Rosengren, Anders H.