The Role of Hepcidin in Iron Metabolism
Open accessAbstract
Hepcidin is the central regulator of systemic iron homeostasis. Dysregulation of hepcidin production results in a variety of iron disorders. Hepcidin deficiency is the cause of iron overload in hereditary hemochromatosis, iron-loading anemias, and hepatitis C. Hepcidin excess is associated with anemia of inflammation, chronic kidney disease and iron-refractory iron deficiency anemia. Diagnostic and therapeutic applications of this new knowledge are beginning to emerge. Dr. Ernest Beutler played a significant role in advancing our understanding of the function of hepcidin. This review is dedicated to his memory.
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Hepcidin expression is suppressed in anemias with ineffective erythropoiesis, decreased by hypoxia, and rapidly increases during infection and inflammation.
“Hepcidin expression is suppressed in anemias with ineffective erythropoiesis, mediated by proteins produced by erythroid precursors.Hypoxia also decreases hepcidin, being modulated by hypoxia-inducible factor.However hepcidin synthesis rapidly increases during infection and inflammation (Nemeth and Ganz, 2009).”
From Iron, Oxidative Stress and Health (2012) · cites this paper as Nemeth and Ganz, 2009
The sections “Hepcidin Regulation by Erythropoietic Activity” and “Hepcidin Regulation by Inflammation” support all three directional claims: hepcidin decreases in anemias with ineffective erythropoiesis and in hypoxia, and rises rapidly during infection and inflammation. The citing sentence states the mechanisms more firmly than the source: erythroid-precursor proteins are proposed mediators, and whether HIF directly regulates hepcidin remains unresolved. (LLM, conf=0.86)
Experimental — accuracy not yet measuredIron export from duodenal enterocytes, macrophages and hepatocytes through FPN1 appears to be a limiting step, modulated by hepcidin.
“Iron export from duodenal enterocytes, macrophages and hepatocytes through FPNI appears to be a limiting step, modulated by the peptide hormone, hepcidin.”
From Iron, Oxidative Stress and Health (2012) · cites this paper as Nemeth and Ganz, 2009
Binding of hepcidin to FPN1 triggers internalization and degradation of the receptor-ligand complex, ceasing cellular iron export.
“Binding of hepcidin to FPN1 triggers the internalization and degradation of the receptor-ligand complex.Once internalized, the hepcidin-FPN1 complex is degraded in lysosomes and cellular iron export ceases”
From Iron, Oxidative Stress and Health (2012) · cites this paper as Nemeth and Ganz, 2009
Disruption of Smad4 and HJV in mice results in iron overload.
“Disruption of Smad 4 and HJV in mice have been reported to result in iron overload (Nemeth and Ganz, 2009).”
From Iron, Oxidative Stress and Health (2012) · cites this paper as Nemeth and Ganz, 2009
Hepcidin expression is regulated by BMP and TfRII-dependent signaling pathways in response to extracellular and intracellular iron.
“Two main iron-related signaling pathways, one involving bone morphogenetic proteins (BMPs -these comprise a group of at least 20 soluble molecules belonging to the transforming growth factor β superfamily) and the other dependent on transferrin receptor II (TfRII) regulate hepcidin regulation.”
From Iron, Oxidative Stress and Health (2012) · cites this paper as Nemeth and Ganz, 2009
Levels of hepcidin are increased during inflammation and decreased by iron insufficiency and erythropoiesis.
“Levels of hepcidin are increased during inflammation and decreased by iron insufficiency and erythropoiesis [45,46,47].”
From Iron as a central player and promising target in cancer progression (2019) · cites this paper as [46]
Iron homeostasis is primarily regulated by hepcidin, a circulating peptide hormone secreted by the liver.
“Iron homeostasis is primarily regulated by hepcidin, a circulating peptide hormone secreted by the liver [241].”
From Nutritional Considerations for the Vegan Athlete (2023) · cites this paper as [241]
Activation of signaling through HFE, TFR1, TFR2, or HJV increases hepcidin transcription in a SMAD-dependent fashion.
“Activation of signaling through the hemochromatosis protein HFE, TFR1, TFR2, or hemojuvelin (HJV), which acts as a co-receptor for bone morphogenetic protein 6 (BMP6), increases hepcidin transcription in a SMAD-dependent fashion.”
From Regulation of erythropoiesis by hypoxia-inducible factors (2013) · cites this paper as [199]
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Cites
Hepcidin Regulates Cellular Iron Efflux by Binding to Ferroportin and Inducing Its Internalization
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“When these mice had an additional gene knocked out encoding a component of the HIF transcriptional complex, hepcidin levels were not suppressed any more. Whether HIF directly regulates hepcidin transcription is still unresolved. One study showed that HIF-1 bound to the mouse and human hepcidin promoters, but another s…”
BackgroundSelf-citationThe iron exporter ferroportin/Slc40a1 is essential for iron homeostasis
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Self-citationImmunoassay for human serum hepcidin
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Self-citationRegulation of iron homeostasis by the hypoxia-inducible transcription factors (HIFs)
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Suppression of hepcidin during anemia requires erythropoietic activity
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Self-citationHemojuvelin is essential for dietary iron sensing, and its mutation leads to severe iron overload
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“HFE, a protein similar to MHC class I molecules, does not bind iron directly but instead interacts with iron-binding proteins, TfR1 and TfR2. It has been proposed that HFE shuttles between TfR1 and TfR2 depending on iron Tf concentrations [”
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Constitutive hepcidin expression prevents iron overload in a mouse model of hemochromatosis
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Self-citationLin, L., Valore, E. V., Nemeth, E., Goodnough, J. B., Gabayan, V., & Ganz, T. (2007) · Blood · doi:10.1182/blood-2007-04-087593 · Cited by 267 · see citing works
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Hepcidin antimicrobial peptide transgenic mice exhibit features of the anemia of inflammation
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Self-citationHepcidin, the hormone of iron metabolism, is bound specifically to α-2-macroglobulin in blood
Pešlová, G., Petrák, J., Kuželová, K., Hrdý, I., Halada, P., Kuchel, P. W., Soe-Lin, S., Ponka, P., Šuťák, R., Becker, E., et al. (2009) · Blood · doi:10.1182/blood-2009-01-201590 · Cited by 127 · see citing works
Hepcidin and iron-loading anemias.
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“regulated by hepcidin, a circulating peptide hormone secreted by the liver [241].”
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“Once internalized, the hepcidin-FPN1 complex is degraded in lysosomes and cellular iron export ceases (Nemeth and Ganz, 2009; Knutson, 2010).”
BackgroundInfluential
- Authors
- Nemeth, E., & Ganz, T.
- Affiliations
- University of California, Los Angeles (US)
- Venue
- Acta Haematologica
- Publisher
- S. Karger AG
- Published
- 2009
- Volume
- 122
- Issue
- 2-3
- Pages
- 78-86
- ISSN
- 0001-5792 (ISSN-L)
- 1421-9662
- PMC
- PMC2855274
- OpenAlex
- W2073271820
- Cited by
- 607
- References
- 25
- Citations by year
- 2026: 18 · 2025: 34 · 2024: 26 · 2023: 54 · 2022: 41 · 2021: 53 · 2020: 45 · 2019: 26 · 2018: 31 · 2017: 20 · 2016: 34 · 2015: 24 · 2014: 35 · 2013: 30 · 2012: 43
- FWCI
- 30.11
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Acta Haematologica (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK082717)
- Topics
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Life Sciences › Neuroscience › Neurology › Neurological diseases and metabolism
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Ferroptosis and cancer prognosis
- Keywords
- hepcidin, iron metabolism, iron homeostasis, hereditary hemochromatosis, iron overload, iron-refractory iron deficiency anemia, anemia of chronic disease, chronic kidney disease, hepatitis C
- MeSH terms
- Homeostasis, Humans, Iron, Models, Molecular, Protein Conformation, Antimicrobial Cationic Peptides, Hepcidins
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