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.
Highlights
Hepcidin has almost exclusively been regarded as an iron-regulatory hormone [1], some studies suggest that it may be functionally promiscuous
We hypothesized that hepcidin senses iron because of the oxidative stress that iron generates through Fenton-type reactions
Of the two paralogous mouse hepcidin genes, mhepc1 is considered functionally equivalent to its human orthologue but is devoid of an antioxidant response element (ARE) in an equivalent position because of a retroviral element inserted within that region of this gene [24]
Summary
Hepcidin has almost exclusively been regarded as an iron-regulatory hormone [1], some studies suggest that it may be functionally promiscuous. Our recent finding that zinc and cadmium can induce hepcidin expression [2], suggests that it might be a sensor-regulator of (other) heavy metal toxins. Hepcidin induction by these metals indicated parallels with MT-1, an Nrf target gene that is synergistically up-regulated by metalresponsive transcription factor -1, MTF-1, to confer protection against cadmium toxicity [3,4]. As the master regulator of cellular stress responses, Nrf confers protection against xenobiotic toxicity, tissue injury and acute inflammation by regulating the expression of cytoprotection genes.
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