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ToolsBernuzzi, Federico, Maertens, Andre, Saha, Shikha, Troncoso-Rey, Perla, Ludwig, Tobias, Hiller, Karsten, Mithen, Richard F., Korcsmaros, Tamas and Traka, Maria H. (2023) Sulforaphane rewires central metabolism to support antioxidant response and achieve glucose homeostasis. Redox Biology, 67. ISSN 2213-2317
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Abstract
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.
| Item Type: | Article |
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| Additional Information: | Data availability statement: The authors have submitted our whole genome transcriptome data in ArrayExpress database and shared the accession IDs in the manuscript. Funding information: This work was supported by the UKRI Biotechnology and Biological Sciences Research Council (BBSRC) Norwich Research Park Biosciences Doctoral Training Partnership grant number BB/M011216/1, the BBSRC Institute Strategic Programme (ISP) Food Innovation and Health BB/R012512/1 and its constituent project BBS/E/F/000PR10347 (Theme 4, Regulation of Metabolic Homeostasis). MHT was additionally supported by the BBSRC Core Capability Grant BB/CCG2260/1 and its constituent project BBS/E/QU/23NB0006 (Food & Nutrition National Bioscience Research Infrastructure). T.K. was supported by the Earlham Institute (Norwich, UK) in partnership with the Quadram Institute (Norwich, UK) and strategically supported by the UKRI BBSRC UK grants (BB/J004529/1, BB/P016774/1, and BB/CSP17270/1). T.K. was also funded by a BBSRC ISP grant for Gut Microbes and Health BB/R012490/1 and its constituent projects, BBS/E/F/000PR10353 and BBS/E/F/000PR10355. |
| Uncontrolled Keywords: | crispr-cas9,glucose,glutathione,methionine,nadph,nrf2,one-carbon (1c) metabolism,pentose phosphate pathway,sulforaphane,organic chemistry ,/dk/atira/pure/subjectarea/asjc/1600/1605 |
| Faculty \ School: | Faculty of Science > School of Biological Sciences Faculty of Science > School of Pharmacy (former - to 2024) |
| Related URLs: | |
| Depositing User: | LivePure Connector |
| Date Deposited: | 19 Feb 2025 09:30 |
| Last Modified: | 19 Feb 2025 16:30 |
| URI: | https://ueaeprints.uea.ac.uk/id/eprint/98548 |
| DOI: | 10.1016/j.redox.2023.102878 |
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