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Phytoestrogens modulate hepcidin expression by Nrf2: Implications for dietary control of iron absorption

Bayele, HK; Balesaria, S; Srai, SK; (2015) Phytoestrogens modulate hepcidin expression by Nrf2: Implications for dietary control of iron absorption. Free Radical Biology and Medicine , 89 pp. 1192-1202. 10.1016/j.freeradbiomed.2015.11.001. Green open access

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Abstract

Hepcidin is a liver-derived antimicrobial peptide that regulates iron absorption and is also an integral part of the acute phase response. In a previous report, we found evidence that this peptide could also be induced by toxic heavy metals and xenobiotics, thus broadening its teleological role as a defensin. However it remained unclear how its sensing of disparate biotic and abiotic stressors might be integrated at the transcriptional level. We hypothesized that its function in cytoprotection may be regulated by NFE2-related factor 2 (Nrf2), the master transcriptional controller of cellular stress defenses. In this report, we show that hepcidin regulation is inextricably linked to the acute stress response through Nrf2 signaling. Nrf2 regulates hepcidin expression from a prototypical antioxidant response element in its promoter, and by synergizing with other basic leucine-zipper transcription factors. We also show that polyphenolic small molecules or phytoestrogens commonly found in fruits and vegetables including the red wine constituent resveratrol can induce hepcidin expression in vitro and post-prandially, with concomitant reductions in circulating iron levels and transferrin saturation by one such polyphenol quercetin. Furthermore, these molecules derepress hepcidin promoter activity when its transcription by Nrf2 is repressed by Keap1. Taken together, the data show that hepcidin is a prototypical antioxidant response or cytoprotective gene within the Nrf2 transcriptional circuitry. The ability of phytoestrogens to modulate hepcidin expression in vivo suggests a novel mechanism by which diet may impact iron homeostasis.

Type: Article
Title: Phytoestrogens modulate hepcidin expression by Nrf2: Implications for dietary control of iron absorption
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.freeradbiomed.2015.11.001
Publisher version: http://dx.doi.org/10.1016/j.freeradbiomed.2015.11....
Language: English
Additional information: © 2015 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Keywords: Antioxidant response element, Hepcidin, Iron overload, Nrf2, Oxidative stress, Phytoestrogen, Polyphenol, Redox regulation
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Structural and Molecular Biology
URI: https://discovery.ucl.ac.uk/id/eprint/1475425
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