title: Phytoestrogens modulate hepcidin expression by Nrf2: Implications for dietary control of iron absorption.
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.
authors.affiliation: Department of Structural and Molecular Biology, Division of Biosciences, University College London, Gower Street, London WC1E 6BT United Kingdom. Electronic address: h.bayele@ucl.ac.uk.
authors.forename: Henry K
authors.initials: HK
authors.lastname: Bayele
authors.affiliation: Department of Structural and Molecular Biology, Division of Biosciences, University College London, Gower Street, London WC1E 6BT United Kingdom.
authors.forename: Sara
authors.initials: S
authors.lastname: Balesaria
authors.affiliation: Department of Structural and Molecular Biology, Division of Biosciences, University College London, Gower Street, London WC1E 6BT United Kingdom. Electronic address: k.srai@ucl.ac.uk.
authors.forename: Surjit K S
authors.initials: SK
authors.lastname: Srai
mesh_terms: D000818:Animals; D061745:Antioxidant Response Elements / Q000235:genetics*; D015153:Blotting, Western; D047369:Chromatin Immunoprecipitation; D024202:Electrophoretic Mobility Shift Assay; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000187:drug effects*; D064451:Hepcidins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007501:Iron / Q000378:metabolism*; D008297:Male; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D048789:Phytoestrogens / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured
chemical_list: C578702:HAMP protein, human; D064451:Hepcidins; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D048789:Phytoestrogens; D012333:RNA, Messenger; D007501:Iron
keywords: Antioxidant response element; Hepcidin; Iron overload; Nrf2; Oxidative stress; Phytoestrogen; Polyphenol; Redox regulation