Evidence for a lack of a direct transcriptional suppression of the iron regulatory peptide hepcidin by hypoxia-inducible factors
Open accessAbstract
BACKGROUND: Hepcidin is a major regulator of iron metabolism and plays a key role in anemia of chronic disease, reducing intestinal iron uptake and release from body iron stores. Hypoxia and chemical stabilizers of the hypoxia-inducible transcription factor (HIF) have been shown to suppress hepcidin expression. We therefore investigated the role of HIF in hepcidin regulation. METHODOLOGY/PRINCIPAL FINDINGS: Hepcidin mRNA was down-regulated in hepatoma cells by chemical HIF stabilizers and iron chelators, respectively. In contrast, the response to hypoxia was variable. The decrease in hepcidin mRNA was not reversed by HIF-1alpha or HIF-2alpha knock-down or by depletion of the HIF and iron regulatory protein (IRP) target transferrin receptor 1 (TfR1). However, the response of hepcidin to hypoxia and chemical HIF inducers paralleled the regulation of transferrin receptor 2 (TfR2), one of the genes critical to hepcidin expression. Hepcidin expression was also markedly and rapidly decreased by serum deprivation, independent of transferrin-bound iron, and by the phosphatidylinositol 3 (PI3) kinase inhibitor LY294002, indicating that growth factors are required for hepcidin expression in vitro. Hepcidin promoter constructs mirrored the response of mRNA levels to interleukin-6 and bone morphogenetic proteins, but not consistently to hypoxia or HIF stabilizers, and deletion of the putative HIF binding motifs did not alter the response to different hypoxic stimuli. In mice exposed to carbon monoxide, hypoxia or the chemical HIF inducer N-oxalylglycine, liver hepcidin 1 mRNA was elevated rather than decreased. CONCLUSIONS/SIGNIFICANCE: Taken together, these data indicate that hepcidin is neither a direct target of HIF, nor indirectly regulated by HIF through induction of TfR1 expression. Hepcidin mRNA expression in vitro is highly sensitive to the presence of serum factors and PI3 kinase inhibition and parallels TfR2 expression.
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- Authors
- Volke, M., Gale, D. P., Maegdefrau, U., Schley, G., Klanke, B., Bosserhoff, A.-K., Maxwell, P. H., Eckardt, K.-U., & Warnecke, C.
- Affiliations
- Friedrich-Alexander-Universität Erlangen-Nürnberg (DE)
- University College London (GB)
- University of Regensburg (DE)
- Corresponding author
- Warnecke, Christina
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2009-11-18
- Volume
- 4
- Issue
- 11
- Pages
- e7875
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC2773926
- OpenAlex
- W1967145414
- Cited by
- 93
- References
- 49
- Citations by year
- 2024: 5 · 2023: 1 · 2022: 6 · 2021: 5 · 2020: 2 · 2019: 2 · 2018: 5 · 2017: 4 · 2016: 9 · 2015: 6 · 2014: 6 · 2013: 12 · 2012: 9
- FWCI
- 6.44
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Apollo (University of Cambridge) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Apollo (cc-by)
- Funders
- Universität Heidelberg
- Topics
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Health Sciences › Medicine › Hematology › Erythropoietin and Anemia Treatment
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Ferroptosis and cancer prognosis
- Keywords
- hepcidin, hypoxia-inducible factor, HIF-1α, HIF-2α, iron regulatory proteins, transferrin receptor 1, transferrin receptor 2, iron metabolism, hypoxia, serum deprivation, PI3-kinase, interleukin-6, bone morphogenetic proteins, anemia of chronic disease, carbon monoxide, hepatoma cells
- MeSH terms
- Animals, Base Sequence, Chromones, Humans, Molecular Sequence Data, Morpholines, Promoter Regions, Genetic, Receptors, Transferrin, Antigens, CD, Interleukin-6, Phosphatidylinositol 3-Kinases, Amino Acid Motifs, Antimicrobial Cationic Peptides, Iron-Regulatory Proteins, Mice, Hypoxia-Inducible Factor 1, Hepcidins
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