Regulation of iron homeostasis by the hypoxia-inducible transcription factors (HIFs)
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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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HIF effects (via hepcidin) mobilisation of iron and can cause expression of inflammatory cytokines such as IL-1, IL-6 and TNF-α under hypoxia, and consequently increases sepsis (HIF-knockout mice are resistant to LPS-induced sepsis).
“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]
Hypoxia-induced proteins HIF-1 or PDGF-BB reduce hepcidin expression, enhancing iron delivery for erythropoiesis.
“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
The von Hippel-Lindau/hypoxia-inducible transcription factor (HIF) system also appears to control hepcidin expression, with HIF1α acting as a repressor when it binds to the hepcidin promoter.
“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]
Experimental studies in cultured cells, animal models and human subjects have established that hepcidin production is O2-sensitive and involves the HIF pathway.
“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]
Nrf2 and AP1 family transcription factors, in conjunction with p300/CBP, are involved in activation of the ARE.
“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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- 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
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › 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
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