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Hypoxia-inducible factor regulates hepcidin via erythropoietin-induced erythropoiesis
Open accessAbstract
Iron demand in bone marrow increases when erythropoiesis is stimulated by hypoxia via increased erythropoietin (EPO) synthesis in kidney and liver. Hepcidin, a small polypeptide produced by hepatocytes, plays a central role in regulating iron uptake by promoting internalization and degradation of ferroportin, the only known cellular iron exporter. Hypoxia suppresses hepcidin, thereby enhancing intestinal iron uptake and release from internal stores. While HIF, a central mediator of cellular adaptation to hypoxia, directly regulates renal and hepatic EPO synthesis under hypoxia, the molecular basis of hypoxia/HIF-mediated hepcidin suppression in the liver remains unclear. Here, we used a genetic approach to disengage HIF activation from EPO synthesis and found that HIF-mediated suppression of the hepcidin gene (Hamp1) required EPO induction. EPO induction was associated with increased erythropoietic activity and elevated serum levels of growth differentiation factor 15. When erythropoiesis was inhibited pharmacologically, Hamp1 was no longer suppressed despite profound elevations in serum EPO, indicating that EPO by itself is not directly involved in Hamp1 regulation. Taken together, we provide in vivo evidence that Hamp1 suppression by the HIF pathway occurs indirectly through stimulation of EPO-induced erythropoiesis.
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In the citing paper
“studies in humans receiving recombinant EPO have not yet shown a significant inverse relationship between serum hepcidin and GDF15 levels”
From Regulation of erythropoiesis by hypoxia-inducible factors (2013) · cites this paper as [208]
In the citing paper
“Hepcidin suppression under conditions of hypoxia and hepatic HIF activation was dependent on erythropoietic activity in the bone marrow.”
From Regulation of erythropoiesis by hypoxia-inducible factors (2013) · cites this paper as [208]
In the citing paper
“We found that recombinant murine GDF15 suppressed hepcidin in Hep3B cells at a concentration of 750 pg/ml.”
From Regulation of erythropoiesis by hypoxia-inducible factors (2013) · cites this paper as [208]
In the citing paper
“found that hypoxia/HIF-mediated suppression of hepcidin required EPO.”
From Regulation of erythropoiesis by hypoxia-inducible factors (2013) · cites this paper as [208]
In the citing paper
“However, we determined that the induction of EPO synthesis alone was not sufficient to suppress hepcidin in this model.”
From Regulation of erythropoiesis by hypoxia-inducible factors (2013) · cites this paper as [208]
In the citing paper
“The latter, however, is most likely a reflection of increased erythropoietic activity.”
From Regulation of erythropoiesis by hypoxia-inducible factors (2013) · cites this paper as [208]
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Citations
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Metadata
- Authors
- Liu, Q., Davidoff, O., Niss, K., & Haase, V. H.
- Affiliations
- Vanderbilt University (US)
- MilliporeSigma (United States) (US)
- Corresponding author
- Haase, Volker H.
- ORCID
- Haase, Volker H.
- Venue
- Journal of Clinical Investigation
- Published
- 2012-11-01
- Volume
- 122
- Issue
- 12
- Pages
- 4635-4644
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC3533545
- OpenAlex
- W2002549547
- Cited by
- 328
- References
- 51
- Citations by year
- 2026: 10 · 2025: 18 · 2024: 18 · 2023: 26 · 2022: 40 · 2021: 25 · 2020: 28 · 2019: 19 · 2018: 22 · 2017: 28 · 2016: 28 · 2015: 20 · 2014: 29 · 2013: 16
- FWCI
- 13.86
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Clinical Investigation (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (R01-DK080821)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK080821, R01DK081646, P30DK020593)
- Topics
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Health Sciences › Medicine › Hematology › Erythropoietin and Anemia Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Hemoglobin structure and function
- Keywords
- hypoxia-inducible factor, hepcidin, erythropoietin, erythropoiesis, iron metabolism, ferroportin, growth differentiation factor 15, hypoxia, iron absorption, liver
- MeSH terms
- Endothelial PAS Domain-Containing Protein 1, Animals, Erythropoiesis, Erythropoietin, Gene Expression Regulation, Humans, Liver, Procollagen-Proline Dioxygenase, Gene Expression, Mice, Knockout, Hepatocytes, Antimicrobial Cationic Peptides, Cell Line, Tumor, Mice, Basic Helix-Loop-Helix Proteins, Basic Helix-Loop-Helix Transcription Factors, Von Hippel-Lindau Tumor Suppressor Protein, Hypoxia-Inducible Factor 1, alpha Subunit, Growth Differentiation Factor 15, Hepcidins, Hypoxia-Inducible Factor-Proline Dioxygenases
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