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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]
Citations
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“Decreased hepcidin is found in all types of hemochromatosis (except ferroportin deficiency).(8) Piperno and coworkers(21) measured the urine hepcidin : ferritin ratio in 88 patients with hemochromatosis (61 C282Y/C282Y, 27 C282Y/H63D).”
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“Furthermore, several studies have shown that flavonoids have a significant impact on hepcidin levels in vivo [58,74].”
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“The 25-amino acid peptide hepcidin, secreted primarily by hepatocytes, has emerged as a central regulator of iron homeostasis (Ganz, 2006; Nemeth & Ganz, 2006).”
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Iron Transport and Signaling in Plants
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“Is a specific hormone, analogous to hepcidin in mammals, involved? In mammals, hepcidin establishes a strong connection between Fe homeostasis and inflammatory responses (Nemeth and Ganz 2006).”
Background2-Oxoglutarate-dependent oxygenases control hepcidin gene expression
Braliou, G. G., Falzacappa, M. V. V., Chachami, G., Casanovas, G., Muckenthaler, M. U., & Simos, G. (2008) · Journal of Hepatology · doi:10.1016/j.jhep.2007.12.021 · Cited by 68
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BackgroundInfluentialHeme Oxygenase-1 and Iron in Liver Inflammation: A Complex Alliance
Immenschuh, S., Baumgart‐Vogt, E., & Mueller, S. (2010) · Current Drug Targets · doi:10.2174/1389450111009011541 · Cited by 71
“Decreased plasma iron concentrations limit the availability of this compound for erythropoiesis ultimately leading to the socalled anemia of chronic disease [34, 41], which could be an important factor for tissue damage by free radicals [42].”
BackgroundPorotic lesions in immature skeletons from Stara Torina, late medieval Serbia
Djuric, M. P., Milovanovic, P. D., Janović, A., Draskovic, M., Djukić, K., & Milenković, P. (2008) · International Journal of Osteoarchaeology · doi:10.1002/oa.955 · Cited by 76
Paesano, R., Berlutti, F., Pietropaoli, M., Pantanella, F., Pacifici, E., Goolsbee, W., & Valenti, P. (2010) · BioMetals · doi:10.1007/s10534-010-9335-z · Cited by 69
“Ferroportin, the only known cellular iron exporter from tissues into blood, has been found in all cell types involved in iron export, including enterocytes, hepatocytes, placental cells (Donovan et al. 2005) and macrophages which recycle 20 mg of iron daily from lysed erythrocytes for erythropoiesis ( Nemeth and Ganz…”
BackgroundIron Homeostasis and Disorders in Dogs and Cats: A Review
McCown, J. L., & Specht, A. J. (2011) · Journal of the American Animal Hospital Association · doi:10.5326/jaaha-ms-5553 · Cited by 73
“Neither the factor that induces hepcidin in response to iron loading nor the factor that inhibits hepcidin in response to anemia or hypoxia have been identified to date.(11,15)”
BackgroundInfluentialIron and hepcidin mediate human colorectal cancer cell growth
Sornjai, W., Long, F. N. V., Pion, N., Pasquer, A., Saurin, J., Marcel, V., Diaz, J., Mertani, H. C., & Smith, D. R. (2020) · Chemico-Biological Interactions · doi:10.1016/j.cbi.2020.109021 · Cited by 66
Ferroptosis inhibitor improves outcome after early and delayed treatment in mild spinal cord injury
Ryan, F., Blex, C., Ngo, T. D., Kopp, M. A., Michalke, B., Venkataramani, V., Curran, L., Schwab, J. M., Ruprecht, K., Otto, C., et al. (2024) · Acta Neuropathologica · doi:10.1007/s00401-024-02758-2 · Cited by 68
“CSF and serum levels of hepcidin, a small peptide hormone that binds to the iron efflux transporter ferroportin and causes its internalization and degradation, thus preventing iron release from cells [39], was not different between SCI and control patients ( p = 0.55, Fig.”
InfluentialRamsay, A. J., Quesada, V., Sánchez, M., Garabaya, C., Sardà, M. P., Baiget, M., Remacha, A. F., Velasco, G., & López-Otín, C. (2009) · Human Molecular Genetics · doi:10.1093/hmg/ddp315 · Cited by 67
“Consistently, HH disorders result from inadequate hepcidin production relative to body iron stores (23).”
BackgroundHolden, V. I., Lenio, S., Kuick, R. D., Ramakrishnan, S. K., Shah, Y. M., & Bachman, M. A. (2014) · Infection and Immunity · doi:10.1128/iai.01849-14 · Cited by 65
“Hepcidin regulates plasma iron concentrations by inhibiting enterocyte uptake of iron and iron recycling by macrophages and is upregulated during infection and inflammation (43).”
BackgroundThe battle for iron in enteric infections
Sousa Gerós, A., Simmons, A., Drakesmith, H., Aulicino, A., & Frost, J. N. (2020) · Immunology · doi:10.1111/imm.13236 · Cited by 58
Relationship between obesity and iron deficiency anemia: is there a role of hepcidin?
Sal, E., Yenicesu, İ., Çelik, N., Paşaoğlu, H., Çelik, B., Paşaoğlu, Ö. T., Kaya, Z., Koçak, Ü., Camurdan, O. M., Bıdecı, A., et al. (2018) · Hematology · doi:10.1080/10245332.2018.1423671 · Cited by 63
“iron from macrophages, hepatocytes and enterocytes [33,34], which result in reduced iron absorption, and sequestration of iron within splenic and hepatic macrophages, less iron is released and more iron is stored, explaining the reduced iron use in the obese.”
BackgroundOhsugi, Y., & Kishimoto, T. (2008) · Expert Opinion on Biological Therapy · doi:10.1517/14712598.8.5.669 · Cited by 62
“This effect may be attributable to inhibition of production of hepcidin (an iron-regulatory peptide secreted by liver cells) [30-33] and/or to the recovery of erythropoietin signal transduction.”
BackgroundLi, L., Hölscher, C., Chen, B., Zhang, Z., & Liu, Y. (2011) · Biological Trace Element Research · doi:10.1007/s12011-011-8967-3 · Cited by 61
“FPN1 is the sole exporter of iron which is responsible for iron absorption from the intestine, recycling of erythrocyte iron by macrophages, and other processes [3, 4]. In most physiological conditions, the transport of iron by FPN1 is regulated by Hepc by inducing the internalization of FPN1 from cell surfaces [ 1 ].”
BackgroundSmall-molecule dissection of BMP signaling
Anderson, G. J., & Darshan, D. (2007) · Nature Chemical Biology · doi:10.1038/nchembio0108-15 · Cited by 61
Plasma hepcidin levels and anemia in old age. The Leiden 85-Plus Study
den Elzen, W. P. J., de Craen, A. J. M., Wiegerinck, E. T. G., Westendorp, R. G. J., Swinkels, D. W., & Gussekloo, J. (2012) · Haematologica · doi:10.3324/haematol.2012.068825 · Cited by 61
“Ferritin (mg/L) 114 (19-425) Low ferritin (<20 mg/L for men and <15 mg/L for women) 19 (4.”
BackgroundInfluentialBlood Lead and Other Metal Biomarkers as Risk Factors for Cardiovascular Disease Mortality
Aoki, Y., Brody, D. J., Flegal, K. M., Fakhouri, T. H. I., Axelrad, D. A., & Parker, J. D. (2016) · Medicine · doi:10.1097/md.0000000000002223 · Cited by 61
“Consequently, we used serum iron, although it has a known limitation of being influenced by inflammation (serum iron decreases in the presence of inflammation).(32) In order to keep the serum iron-CVD mortality follow-up through 2011.”
MethodLin, D., & Medeiros, D. M. (2023) · Nutrition Research · doi:10.1016/j.nutres.2023.02.007 · Cited by 62
Aslam, M., Frazer, D., Faria, N., Bruggraber, S., Wilkins, S. J., Mirciov, C. S. G., Powell, J., Anderson, G. J., & Pereira, D. I. A. (2014) · The FASEB Journal · doi:10.1096/fj.14-251520 · Cited by 57
“Since Fpn is the only known mammalian iron export protein (29), we investigated the absorption of nanoFe(3) in intestine-specific FpnKO mice and littermate controls.”
BackgroundMoayedi, B., Gharagozloo, M., Esmaeil, N., Maracy, M. R., Hoorfar, H., & Jalaeikar, M. (2012) · European Journal Of Haematology · doi:10.1111/ejh.12061 · Cited by 59
Paesano, R., Pacifici, E., Benedetti, S., Berlutti, F., Frioni, A., Polimeni, A., & Valenti, P. (2014) · BioMetals · doi:10.1007/s10534-014-9723-x · Cited by 59
“Therefore, anaemia of inflammation is characterized by ID despite adequate iron stores (Nemeth and Ganz 2006).”
BackgroundTarifeño-Saldivia, E., Aguilar, A., Contreras, D., Mercado, L. A., Lange, B. M., Márquez, K., Henríquez, A., Riquelme-Vidal, C., & Boltaña, S. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.01296 · Cited by 59
“Hepcidin gene transcription is regulated by iron levels, a rise on the iron level in plasma induce upregulation hepcidin mRNAs (10), in contrast, when iron level are restricted expression of hepcidin is inhibited and, therefore, iron is released from tissues (11).”
BackgroundRefining Treatment Strategies for Iron Deficient Athletes
McCormick, R., Sim, M., DAWSON, B. T., & Peeling, P. (2020) · Sports Medicine · doi:10.1007/s40279-020-01360-2 · Cited by 58
“sumption of a dose of iron > 40 mg, likely to be a result of both the mucosal block mechanism [94, 95], and the influence of homeostatic elevations in hepcidin [96].”
BackgroundPrakash, D. (2012) · Critical Care Clinics · doi:10.1016/j.ccc.2012.04.012 · Cited by 60
Paesano, R., Pietropaoli, M., Gessani, S., & Valenti, P. (2008) · Biochimie · doi:10.1016/j.biochi.2008.06.004 · Cited by 59
“In inflammatory disorders and infections, cytokine-induced hepcidin up-modulation contributes to the development of anaemia of inflammation, characterised by hypoferremia and anaemia despite adequate iron stores [34].”
BackgroundGesquiere, I., Foulon, V., Augustijns, P., Gils, A., Lannoo, M., der Schueren, B. V., & Matthys, C. (2016) · Clinical Nutrition · doi:10.1016/j.clnu.2016.08.009 · Cited by 58
“In this study, we have included status markers that are standardly determined in clinical practice and we have collected blood samples to determine hepcidin as hepcidin has a central role in iron metabolism [7].”
MethodBarroso, C., Carvalho, P., Nunes, M., Gonçalves, G. S., Rodrigues, P., & Neves, J. V. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.754437 · Cited by 58
“A biological increase in hamp1 levels is known to occur in response to conditions of iron overload, to signal the body to limit further iron absorption (16, 17, 52), as well as during various infectious diseases, as a mechanism to limit pathogen proliferation (26, 53–55).”
BackgroundInfluentialUnderstanding the Structure/Activity Relationships of the Iron Regulatory Peptide Hepcidin
Clark, R. J., Tan, C. C., Preza, G. C., Nemeth, E., Ganz, T., & Craik, D. J. (2011) · Chemistry & Biology · doi:10.1016/j.chembiol.2010.12.009 · Cited by 55
“The peptide hormone hepcidin is a key regulator of iron homeostasis and is produced by the liver in response to high plasma iron levels and inflammatory stimuli (Ganz, 2008; Nemeth and Ganz, 2006).”
BackgroundSelf-citationThe struggle for iron: gastrointestinal microbes modulate the host immune response during infection
Markel, T. A., Crisostomo, P. R., Wang, M., Herring, C. M., Meldrum, K. K., Lillemoe, K. D., & Meldrum, D. R. (2007) · Journal of Leukocyte Biology · doi:10.1189/jlb.0906579 · Cited by 57
“This adaptation limits iron availability to invading organisms and therefore, contributes to host defense [104].”
BackgroundTodd, J. J., McSorley, E. M., Pourshahidi, L. K., Madigan, S. M., Laird, E. J., Healy, M., & Magee, P. J. (2016) · European Journal of Nutrition · doi:10.1007/s00394-016-1202-4 · Cited by 58
Zhang, H., Wang, A., Shen, G., Wang, X. L., Liu, G., Yang, F., Chen, B., Wang, M., & Xu, Y. (2021) · Aging · doi:10.18632/aging.202817 · Cited by 55
“Hepcidin is an iron reducing hormone mainly synthesized and secreted by the liver and excreted in the urine (macrophages can also synthesize and secrete it in small amounts) [21].”
Micronutrient Deficiency in Children and Adolescents with Obesity—A Narrative Review
Calcaterra, V., Verduci, E., Milanta, C., Agostinelli, M., Todisco, C. F., Bona, F., Dolor, J., Mendola, A. L., Tosi, M., & Zuccotti, G. (2023) · Children · doi:10.3390/children10040695 · Cited by 71
Schaer, C. A., Vallelian, F., Imhof, A., Schoedon, G., & Schaer, D. J. (2007) · Journal of Leukocyte Biology · doi:10.1189/jlb.0407226 · Cited by 56
“metal transporter 1 (DMT-1), and the iron exporter ferroportin [12–21].”
BackgroundDecreased expression of ferroportin in prostate cancer
Xue, D., Zhou, C., Shi, Y., Lü, H., & He, X. (2015) · Oncology Letters · doi:10.3892/ol.2015.3363 · Cited by 53
“Hepcidin, predominantly synthesized in the liver, is the principal regulator of systemic iron homeostasis, and acts by inhibiting intestinal iron absorption, iron recycling by macrophages, and iron mobilization from hepatic stores (5).”
BackgroundLiver dysfunction and its nutritional implications in heart failure
Valentová, M., von Haehling, S., Doehner, W., Murín, J., Anker, S. D., & Sandek, A. (2012) · Nutrition · doi:10.1016/j.nut.2012.06.002 · Cited by 54
“Hepcidin binding to the transmembrane iron transporter ferroportin causes its internalization and degradation [70].”
Background
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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