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Regulation of iron homeostasis by the hypoxia-inducible transcription factors (HIFs)
Open accessAbstract
Iron is essential for many biological processes, including oxygen delivery, and its supply is tightly regulated. Hepcidin, a small peptide synthesized in the liver, is a key regulator of iron absorption and homeostasis in mammals. Hepcidin production is increased by iron overload and decreased by anemia and hypoxia; but the molecular mechanisms that govern the hepcidin response to these stimuli are not known. Here we establish that the von Hippel-Lindau/hypoxia-inducible transcription factor (VHL/HIF) pathway is an essential link between iron homeostasis and hepcidin regulation in vivo. Through coordinate downregulation of hepcidin and upregulation of erythropoietin and ferroportin, the VHL-HIF pathway mobilizes iron to support erythrocyte production.
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“In particular, HIF effects (via hepcidin) the mobilisation or iron and can cause the expression of inflammatory cytokines such as IL-1, IL-6 and TNF-α [2254-2256] under conditions (hypoxia) where superoxide and peroxide production are likely to be increased, and consequently increases sepsis (in that HIF-knockout mice are resistant to LPS-induced sepsis [2254,2255]).”
From Iron behaving badly: inappropriate iron chelation as a major contributor to the aetiology of vascular and other progressive inflammatory and degenerative diseases (2009) · cites this paper as [2254]
In the citing paper
“and several proteins induced by hypoxia such as hypoxia inducible factor-1 (HIF-1) or platelet derived growth factor BB (PDGF-BB) reduce hepcidin expression, thereby enhancing iron delivery for erythropoiesis (Peyssonnaux et al., 2007; Sonnweber et al., 2014).”
From The Role of Iron Regulation in Immunometabolism and Immune-Related Disease (2019) · cites this paper as Peyssonnaux et al., 2007
In the citing paper
“The von Hippel-Lindau/hypoxia-inducible transcription factor (HIF) system also appears to control hepcidin expression, with HIF1␣ acting as a repressor when it binds to the hepcidin promoter.109”
From Forging a field: the golden age of iron biology. (2008) · cites this paper as [109]
In the citing paper
“Experimental studies in cultured cells, in animal models and in human subjects have established that hepcidin production is O2-sensitive and involves the HIF pathway.”
From Regulation of erythropoiesis by hypoxia-inducible factors (2013) · cites this paper as [193]
In the citing paper
“Subsequent investigation revealed that Nrf2 and AP1 family transcription factors, in conjunction with transcriptional coactivator p300/CBP, are involved in the activation of the ARE (246, 302, 306, 307)”
From Intracellular iron transport and storage: from molecular mechanisms to health implications (2008) · cites this paper as [246]
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Metadata
- Authors
- Peyssonnaux, C., Zinkernagel, A. S., Schuepbach, R. A., Rankin, E., Vaulont, S., Haase, V. H., Nizet, V., & Johnson, R. S.
- Affiliations
- University of California San Diego (US)
- Scripps Research Institute (US)
- University of Pennsylvania (US)
- Centre National de la Recherche Scientifique (FR)
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2007-07-02
- Volume
- 117
- Issue
- 7
- Pages
- 1926-1932
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC1884690
- OpenAlex
- W2116374020
- Cited by
- 639
- References
- 36
- Citations by year
- 2026: 14 · 2025: 17 · 2024: 19 · 2023: 25 · 2022: 26 · 2021: 34 · 2020: 32 · 2019: 18 · 2018: 36 · 2017: 28 · 2016: 31 · 2015: 30 · 2014: 35 · 2013: 39 · 2012: 43
- FWCI
- 33.22
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Zurich Open Repository and Archive (University of Zurich) (acceptedVersion, other-oa)
- Zurich Open Repository and Archive (University of Zurich) (submittedVersion, other-oa)
- Zurich Open Repository and Archive (University of Zurich)
- Funders
- National Institutes of Health
- National Cancer Institute (R01CA100787)
- National Institute of Allergy and Infectious Diseases (AI060840, R01AI060840)
- National Institute of Diabetes and Digestive and Kidney Diseases (R21DK073467)
- Topics
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Health Sciences › Medicine › Hematology › Erythropoietin and Anemia Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Ferroptosis and cancer prognosis
- Keywords
- iron homeostasis, hypoxia-inducible factor, VHL, hepcidin, erythropoietin, ferroportin, iron mobilization, erythropoiesis, anemia, iron overload, hypoxia
- MeSH terms
- Ferroportin, Albumins, Animals, Base Sequence, Homeostasis, Humans, Iron, Liver, Mice, Inbred C57BL, Mice, Transgenic, Molecular Sequence Data, Polycythemia, Promoter Regions, Genetic, Protein Binding, Down-Regulation, Up-Regulation, Gene Deletion, Integrases, Hepatocytes, Antimicrobial Cationic Peptides, Cation Transport Proteins, Mice, Hypoxia-Inducible Factor 1, Von Hippel-Lindau Tumor Suppressor Protein, Hepcidins
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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