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Regulation of Iron Metabolism by Hepcidin
Abstract
▪ Abstract Hepcidin, a peptide hormone made in the liver, is the principal regulator of systemic iron homeostasis. Hepcidin controls plasma iron concentration and tissue distribution of iron by inhibiting intestinal iron absorption, iron recycling by macrophages, and iron mobilization from hepatic stores. Hepcidin acts by inhibiting cellular iron efflux through binding to and inducing the degradation of ferroportin, the sole known cellular iron exporter. Synthesis of hepcidin is homeostatically increased by iron loading and decreased by anemia and hypoxia. Hepcidin is also elevated during infections and inflammation, causing a decrease in serum iron levels and contributing to the development of anemia of inflammation, probably as a host defense mechanism to limit the availability of iron to invading microorganisms. At the opposite side of the spectrum, hepcidin deficiency appears to be the ultimate cause of most forms of hemochromatosis, either due to mutations in the hepcidin gene itself or due to mutations in the regulators of hepcidin synthesis. The emergence of hepcidin as the pathogenic factor in most systemic iron disorders should provide important opportunities for improving their diagnosis and treatment.
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“Once secreted, HAMP circulates and reaches the duodenum and spleen where it tags the iron exporter FPN1 for internalization from the cell membrane and subsequent degradation in the proteasome (Nemeth and Ganz, 2006).”
From Iron in infection and immunity (2020) · cites this paper as Nemeth and Ganz, 2006
In the citing paper
“The presence of Fpn1 in the absorptive epithelium is under negative control of hepcidin, which is mainly secreted by hepatocytes in response to high circulating and tissue amounts of iron or upon stimulation by inflammatory mediators [171, 229].”
From “Pumping iron”—how macrophages handle iron at the systemic, microenvironmental, and cellular levels (2017) · cites this paper as [171]
In the citing paper
“The key to systemic iron homeostasis lies with hepcidin (HAMP) regulation. 37”
From The battle for iron in enteric infections (2020) · cites this paper as [37]
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“Our results are concordant with emerging evidence of the importance of ferroportin in ironhomeostasis, both at an organismal level in transmitting the signals from hepcidin to the systemic iron-regulatory network (46) and in regulating iron homeostasis in cells (17).”
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Pérez-Torres, I., Castrejón-Téllez, V., Soto, M. E., Rubio-Ruiz, M. E., Manzano-Pech, L., & Guarner‐Lans, V. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22041786 · Cited by 437
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“Hypoxia therefore reduces hepcidin synthesis by decreasing BMP-6 by two mechanisms: HJV antagonism by sHJV, and augmentation of martriptase-2 cleavage (122).”
BackgroundTransfusion and risk of acute kidney injury in cardiac surgery
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17β-Estradiol Inhibits Iron Hormone Hepcidin Through an Estrogen Responsive Element Half-Site
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“control of hepcidin, which is mainly secreted by hepatocytes in response to high circulating and tissue amounts of iron or upon stimulation by inflammatory mediators [171, 229].”
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“Fetal-derived hepcidin may play a role in the regulation of Fpn expressed at the basolateral side of the syncytiotrophoblast [31] and determine the rate of iron entry into fetal circulation [35].”
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Self-citationIron in arterial plaque: A modifiable risk factor for atherosclerosis
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“Hepcidin has been established as a key regulator of iron absorption from the enterocytes and release from the macrophages; however, it has not entered routine testing [16,21].”
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“Hepcidin deficiency is a characteristic of mutations in the HAMP (hepcidin antimicrobial peptide) gene but most patients with genetic hemochromatosis have alterations in the HFE (high iron Fe) gene, or, rarely in the transferrin receptor 2 (TFR2) or hemojuvelin (HJV) genes, suggesting that these proteins are involved…”
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“Hepcidin is also thought to play a regulatory role in iron metabolism by directly affecting the ferroportin transporter within the mucosal basolateral membrane and by preventing iron efflux into the blood (40).”
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“Iron is an essential element that acts as a key component of oxygen-carrying proteins, is a vital player in cellular metabolism, and is essential to cell growth and differentiation (1).”
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Elevated Systemic Hepcidin and Iron Depletion in Obese Premenopausal Females
Tussing-Humphreys, L. M., Nemeth, E., Fantuzzi, G., Freels, S. A., Guzman, G., Holterman, A. L., & Braunschweig, C. L. (2009) · Obesity · doi:10.1038/oby.2009.319 · Cited by 170
“It is increased by inflammation and elevated body iron levels and decreased by erythropoietic activity and hypoxia (13,14).”
InfluentialSelf-citationNorthrop‐Clewes, C. A. (2008) · Annals of Clinical Biochemistry International Journal of Laboratory Medicine · doi:10.1258/acb.2007.007167 · Cited by 164
Selective modulation of TLR4-activated inflammatory responses by altered iron homeostasis in mice
Wang, L., Harrington, L., Trebicka, E., Shi, H. N., Kagan, J. C., Hong, C. C., Lin, H. Y., Babitt, J. L., & Cherayil, B. J. (2009) · Journal of Clinical Investigation · doi:10.1172/jci39939 · Cited by 162
“Hepcidin expression is upregulated by iron loading and inflammation, whereas it is inhibited by iron deficiency, anemia, and hypoxia (14, 15).”
Ferroportin is a manganese‐responsive protein that decreases manganese cytotoxicity and accumulation
Yin, Z., Jiang, H., Lee, E.-S., Ni, M., Erikson, K. M., Milatović, D., Bowman, A. B., & Aschner, M. (2009) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2009.06534.x · Cited by 162
“2003), and post-translational regulation by the action of hepcidin (Nemeth and Ganz 2006).”
BackgroundWang, L., Johnson, E. E., Shi, H. N., Walker, W. A., Wessling-Resnick, M., & Cherayil, B. J. (2008) · The Journal of Immunology · doi:10.4049/jimmunol.181.4.2723 · Cited by 159
“Hepcidin production increases with iron loading and inflammation, and decreases with iron deficiency, anemia, and hypoxia (16, 17).”
BackgroundA genome-wide association analysis of serum iron concentrations
Tanaka, T., Roy, C. N., Yao, W., Matteini, A. M., Semba, R. D., Arking, D. E., Walston, J. D., Fried, L. P., Singleton, A., Guralnik, J. M., et al. (2009) · Blood · doi:10.1182/blood-2009-07-232496 · Cited by 162
Iron and Zinc Nutrition in the Economically-Developed World: A Review
Lim, K., Riddell, L. J., Nowson, C. A., Booth, A., & Szymlek‐Gay, E. A. (2013) · Nutrients · doi:10.3390/nu5083184 · Cited by 152
“Higher concentrations of hepcidin prevent ingested iron from entering the bloodstream by trapping iron in enterocytes which are naturally shed every two days [112], thereby preventing body iron from escalating to dangerous levels.”
BackgroundReticulocyte hemoglobin content
Mast, A. E., Blinder, M. A., & Dietzen, D. J. (2007) · American Journal of Hematology · doi:10.1002/ajh.21090 · Cited by 151
“Hepcidin is an acute phase reactant that prevents absorption of iron from the gastrointestinal tract, its release from hepatic stores, and its recycling within the reticuloendothelial system [15].”
BackgroundInsulin resistance impairs nigrostriatal dopamine function
Morris, J. K., Bomhoff, G. L., Gorres, B. K., Davis, V. A., Kim, J., Lee, P., Brooks, W. M., Gerhardt, G. A., Geiger, P. C., & Stanford, J. A. (2011) · Experimental Neurology · doi:10.1016/j.expneurol.2011.06.005 · Cited by 155
“We also measured SN levels of hepcidin, which can control ferroportin through posttranslational modification (Nemeth and Ganz, 2006).”
MethodRhodes, M., Kopsombut, P., Bondurant, M. C., Price, J. O., & Koury, M. J. (2007) · Blood · doi:10.1182/blood-2007-06-098178 · Cited by 149
“Three other proteins found on the surface of stromal macrophages have been associated with enhanced proliferation of erythroid progenitor cells: ( 1 ) c-kit ligand (stem-cell factor), a transmembrane protein that binds c-kit (stem-cell factor receptor) on erythroid cells.”
InfluentialStefanova, D., Raychev, A., Arezes, J., Ruchala, P., Gabayan, V., Skurnik, M., Dillon, B. J., Horwitz, M. A., Ganz, T., Bulut, Y., et al. (2017) · Blood · doi:10.1182/blood-2017-03-772715 · Cited by 145
Self-citationIron regulatory proteins secure mitochondrial iron sufficiency and function
Galy, B., Ferring-Appel, D., Sauer, S. W., Kaden, S., Lyoumi, S., Puy, H., Kölker, S., Gröne, H.-J., & Hentze, M. W. (2010) · Cell Metabolism · doi:10.1016/j.cmet.2010.06.007 · Cited by 147
“At the systemic level, the hepatic ‘‘iron hormone’’ hepcidin (Hamp) has emerged as the key regulator of blood iron levels (Nemeth and Ganz, 2006).”
BackgroundDomenico, I. D., Lo, E., Ward, D. M., & Kaplan, J. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0900453106 · Cited by 143
“Western analysis was performed using either mouse anti-FLAG antibody (1:10,000; Sigma-Aldrich), rabbit anti-Fpn (1:1000), mouse anti-tubulin (1:1000; GeneTex), mouse anti-phosphotyrosine clone 16F4 (1:500; Calbiochem), or mouse anti-Jak2 (1:1000; Cell Signaling), followed by either peroxidase-conjugated goat anti-mous…”
BackgroundMethodInfluentialMacrophage Iron, Hepcidin, and Atherosclerotic Plaque Stability
Sullivan, J. L. (2007) · Experimental Biology and Medicine · doi:10.3181/0703-mr-54 · Cited by 147
“Lower levels are associated with anemia, hypoxia, iron deficiency, and hereditary hemochromatosis (24, 26, 27, 32).”
BackgroundCrusade for iron: iron uptake in unicellular eukaryotes and its significance for virulence
Šuťák, R., Lesuisse, E., Tachezy, J., & Richardson, D. R. (2008) · Trends in Microbiology · doi:10.1016/j.tim.2008.03.005 · Cited by 145
The pathophysiology and pharmacology of hepcidin
Ruchala, P. P., & Nemeth, E. (2014) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2014.01.004 · Cited by 141
“Hepcidin production increases in response to iron loading [11,12], and this prevents further absorption of dietary iron and the development of iron overload.”
BackgroundSelf-citationEstrogen Regulates Hepcidin Expression via GPR30-BMP6-Dependent Signaling in Hepatocytes
Ikeda, Y., Tajima, S., Izawa-Ishizawa, Y., Kihira, Y., Ishizawa, K., Tomita, S., Tsuchiya, K., & Tamaki, T. (2012) · PLoS ONE · doi:10.1371/journal.pone.0040465 · Cited by 140
“Hepcidin is a secreted protein derived from hepatocytes, and it has been identified as an important regulator of iron metabolism [4].”
BackgroundIncreased iron content and RNA oxidative damage in skeletal muscle with aging and disuse atrophy
Hofer, T., Marzetti, E., Xu, J., Seo, A. Y., Güleç, Ş., Knutson, M. D., Leeuwenburgh, C., & Dupont‐Versteegden, E. E. (2008) · Experimental Gerontology · doi:10.1016/j.exger.2008.02.007 · Cited by 140
“, 2005), the master regulator of whole-body iron homeostasis (Nemeth and Ganz, 2006).”
Andang’o, P. E. A., Osendarp, S. J. M., Ayah, R., West, C. E., Mwaniki, D. L., Wolf, C. A. D., Kraaijenhagen, R. J., Kok, F. J., & Verhoef, H. (2007) · The Lancet · doi:10.1016/s0140-6736(07)60817-4 · Cited by 133
Mitchell, C. J., Shawki, A., Ganz, T., Nemeth, E., & Mackenzie, B. (2014) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00348.2013 · Cited by 132
Self-citationMatriptase-2 (TMPRSS6): a proteolytic regulator of iron homeostasis
Ramsay, A. J., Hooper, J. D., Folgueras, A. R., Velasco, G., & López-Otín, C. (2009) · Haematologica · doi:10.3324/haematol.2008.001867 · Cited by 134
“Consistently, HH disorders result from inadequate hepcidin production relative to body iron stores.(99) Conversely, elevated hepcidin levels have been described in iron deficiency anemia patients that are insensitive to oral iron therapy and”
BackgroundDavid, S., Jhelum, P., Ryan, F., Jeong, S. Y., & Kroner, A. (2021) · Antioxidants and Redox Signaling · doi:10.1089/ars.2021.0218 · Cited by 134
“The cell surface localization of Fpn is also regulated by a 25 amino acid peptide hormone called hepcidin, which is produced by the liver and delivered systemically via the circulation (49, 126).”
Iron and Porphyrin Trafficking in Heme Biogenesis
Schultz, I. J., Chen, C., Paw, B. H., & Hamza, I. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.r110.119503 · Cited by 131
Sendamarai, A. K., Ohgami, R. S., Fleming, M. D., & Lawrence, C. M. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0801318105 · Cited by 134
The Chelating Ability of Plant Polyphenols Can Affect Iron Homeostasis and Gut Microbiota
Scarano, A., Laddomada, B., Blando, F., Santis, S. D., Verna, G., Chieppa, M., & Santino, A. (2023) · Antioxidants · doi:10.3390/antiox12030630 · Cited by 137
“At a systemic level, an important protein regulating iron homeostasis is represented by hepcidin, synthetized by the liver, which regulates the iron absorption, distribution, and storage in the different body districts [29].”
BackgroundHepcidin antagonists for potential treatments of disorders with hepcidin excess
Poli, M., Asperti, M., Ruzzenenti, P., Regoni, M., & Arosio, P. (2014) · Frontiers in Pharmacology · doi:10.3389/fphar.2014.00086 · Cited by 124
“Although mammalian hepcidin attracted most interest, it should be mentioned that hepcidin has been described also in fishes, where the size and cysteines are conserved, but the overall amino acid sequence identity with the human one is only 50% (Nemeth and Ganz, 2006).”
BackgroundMembrane-Anchored Serine Proteases in Vertebrate Cell and Developmental Biology
Szabo, R., & Bugge, T. H. (2011) · Annual Review of Cell and Developmental Biology · doi:10.1146/annurev-cellbio-092910-154247 · Cited by 125
“Both processes are controlled systemically by a hepatic peptide hormone, hepcidin (reviewed in Andrews 2008, Nemeth & Ganz 2006).”
BackgroundExcess Adiposity, Inflammation, and Iron-Deficiency in Female Adolescents
Tussing-Humphreys, L. M., Liang, H., Nemeth, E., Freels, S. A., & Braunschweig, C. A. (2009) · Journal of the American Dietetic Association · doi:10.1016/j.jada.2008.10.044 · Cited by 127
“Hepcidin controls dietary iron absorption and distribution of iron in the body by regulating ferroportin, the channel that exports iron from cells into plasma ( 32 ).”
BackgroundSelf-citationIron Regulatory Proteins: From Molecular Mechanisms to Drug Development
Recalcati, S., Minotti, G., & Cairo, G. (2010) · Antioxidants and Redox Signaling · doi:10.1089/ars.2009.2983 · Cited by 127
“5) (142).”
InfluentialKroot, J. J., Hendriks, J. C. M., Laarakkers, C. M., Klaver, S. M., Kemna, E., Tjalsma, H., & Swinkels, D. W. (2009) · Analytical Biochemistry · doi:10.1016/j.ab.2009.03.039 · Cited by 121
“The typical response of the body to low iron levels is to decrease hepcidin production, which in turn increases iron absorption from the diet and iron release from macrophages [20].”
BackgroundIron-Refractory Iron Deficiency Anemia
Finberg, K. E. (2009) · Seminars in Hematology · doi:10.1053/j.seminhematol.2009.06.006 · Cited by 119
Benefits and Risks of Iron Supplementation in Anemic Neonatal Pigs
Lipiński, P., Starzyński, R. R., Canonne‐Hergaux, F., Tudek, B., Oliński, R., Kowalczyk, P., Dziaman, T., Thibaudeau, O., Gralak, M. A., Smuda, E., et al. (2010) · American Journal Of Pathology · doi:10.2353/ajpath.2010.091020 · Cited by 119
Retinal iron homeostasis in health and disease
Song, D., & Dunaief, J. L. (2013) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2013.00024 · Cited by 122
“Hereditary hemochromatosis can also result from mutations in Hepc, hemojuvelin (responsible for juvenile hemochromatosis), or TfR 2 (Pietrangelo, 2005; Nemeth and Ganz, 2006).”
BackgroundZhang, A., Anderson, S. A., Wang, J., Yang, F., DeMaster, K., Ahmed, R., Nizzi, C. P., Eisenstein, R. S., Tsukamoto, H., & Enns, C. A. (2010) · Blood · doi:10.1182/blood-2010-06-287292 · Cited by 125
Metadata
- Authors
- Nemeth, E., & Ganz, T.
- Affiliations
- University of California, Los Angeles (US)
- Venue
- Annual Review of Nutrition
- Publisher
- Annual Reviews
- Published
- 2006-08-01
- Volume
- 26
- Issue
- 1
- Pages
- 323-342
- ISSN
- 0199-9885 (ISSN-L)
- 1545-4312
- OpenAlex
- W2153145418
- Cited by
- 756
- References
- 89
- Citations by year
- 2026: 10 · 2025: 26 · 2024: 26 · 2023: 32 · 2022: 28 · 2021: 39 · 2020: 47 · 2019: 27 · 2018: 29 · 2017: 33 · 2016: 38 · 2015: 38 · 2014: 57 · 2013: 39 · 2012: 41
- FWCI
- 6.08
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Annual Review of Nutrition (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (DK065029, R01DK065029)
- Topics
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Ferroptosis and cancer prognosis
- Life Sciences › Neuroscience › Neurology › Neurological diseases and metabolism
- Keywords
- hepcidin, iron metabolism, iron homeostasis, ferroportin, intestinal iron absorption, hepatic iron stores, anemia of chronic disease, iron deficiency anemia, hemochromatosis, hypoxia, infection, inflammation, iron efflux
- MeSH terms
- Hemochromatosis, Homeostasis, Humans, Inflammation, Iron, Iron Metabolism Disorders, Antimicrobial Cationic Peptides, Hepcidins
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