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

Autor: Henry K, Bayele, Sara, Balesaria, Surjit K S, Srai
Rok vydání: 2015
Předmět:
Male
GAPDH
glyceraldehyde 3-phosphate dehydrogenase
Hepcidin
Electrophoretic Mobility Shift Assay
HO-1
heme oxygenase 1
DMSO
dimethyl sulfoxide
MT-1
metallothionein 1
GST
glutathione S-transferase
Rats
Sprague-Dawley
PCR
polymerase chain reaction
Antioxidant response element
Tumor Cells
Cultured
Iron overload
QR1
quinone reductase 1
Reverse Transcriptase Polymerase Chain Reaction
BRM
Brahma
tBHQ
tert-butyl hydroquinone
food and beverages
Original Contribution
Bach1
BTB and CNC homology 1 basic leucine zipper transcription factor 1
Flow Cytometry
HepcARE
Hepcidin antioxidant response element
EMSA
electrophoretic mobility shifts assay
ChIP
chromatin immunoprecipitation
Keap1
Kelch-like ECH-associated protein 1
IL-6
interleukin 6
c-Fos
Finkel-Biskis-Reilly osteogenic sarcoma
Phytoestrogen
LPS
lipopolysaccharide
qPCR
quantitative polymerase chain reaction
Nrf2
NF-E2-related factor 2
Polyphenol
Chromatin Immunoprecipitation
RIPA
Radio-immunoprecipitation assay
NF-E2-Related Factor 2
β-TrCP
β-transducin repeat-containing protein
Iron
Blotting
Western
IgG
immunoglobulin G
Phytoestrogens
ARE
antioxidant response element
Maf
musculo-aponeurotic fibrosarcoma
Real-Time Polymerase Chain Reaction
digestive system
Nrf2
BRG1
Brahma-related gene-1
ER
endoplasmic reticulum
RT-PCR
Real time-PCR
Hamp
hepcidin antimicrobial peptide
Hepcidins
SCF
Skp
Cullin
F-box
Animals
Humans
c-Jun
Jun proto-oncogene
RNA
Messenger
Antioxidant Response Elements
Rats
FeNTA
Fe(III) nitrilotriacetic acid
Gene Expression Regulation
Oxidative stress
Redox regulation
Ct
cycle threshold
Zdroj: Free Radical Biology & Medicine
ISSN: 1873-4596
Popis: 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.
Graphical abstract fx1
Highlights • Nrf2 regulates HAMP transcription. • Phytoestrogens differentially induce HAMP transcription by Nrf2. • Post-prandial hepcidin induction reduces serum iron and transferrin saturation. • Nrf2 knockout results in iron-overload in mouse embryonic fibroblasts.
Databáze: OpenAIRE
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