Cited by 761Iron Metabolism and DisordersFerroptosis and cancer prognosisNeurological diseases and metabolism

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Regulation of Iron Metabolism by Hepcidin

Nemeth, Elizabeta, Ganz, Tomas·2006·Annual Review of Nutrition

DOI 10.1146/annurev.nutr.26.061505.111303

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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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Background
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REVIEW OF LABORATORY AND NECROPSY EVIDENCE FOR IRON STORAGE DISEASE ACQUIRED BY BROWSER RHINOCEROSES
Paglia, D. E., & Tsu, I.-H. (2012) · Journal of Zoo and Wildlife Medicine · doi:10.1638/2011-0177.1 · Cited by 36
“This was engendered by a recent series of elegant investigations revealing the crucial roles of hepcidin and ferroportin in maintaining iron balance.(14,47,48) Hepcidin, a 25amino acid antimicrobial peptide, has been identified as the principal hormone controlling plasma iron levels by its interaction with ferroportin…”
Background
Induced‑iron overdose modulate the immune response in Atlantic salmon increasing the susceptibility to Piscirickettsia salmonis infection
Valenzuela‐Muñoz, V., Valenzuela‐Miranda, D., Gonçalves, A. T., Novoa, B., Figueras, A. J., & Gallardo‐Escárate, C. (2020) · Aquaculture · doi:10.1016/j.aquaculture.2020.735058 · Cited by 36
Blood Iron Homeostasis: Newly Discovered Proteins and Iron Imbalance
Bleackley, M. R., Wong, A. Y. K., Hudson, D. M., Wu, C., & MacGillivray, R. T. A. (2009) · Transfusion Medicine Reviews · doi:10.1016/j.tmrv.2008.12.001 · Cited by 38
Case studies: iron
Lynch, S. R. (2011) · American Journal of Clinical Nutrition · doi:10.3945/ajcn.110.005959 · Cited by 35
“3) Plasma and urinary hepcidin concentrations (16).”
Critical Review of Strategies to Prevent and Control Iron Deficiency in Children
Lynch, S. R., Stoltzfus, R. J., & Rawat, R. (2007) · Food and Nutrition Bulletin · doi:10.1177/15648265070284s413 · Cited by 36
“In the absence of disorders of iron metabolism and inflammatory diseases, absorption is regulated primarily by the size of the stores and the rate of erythropoiesis [3, 4].”
Background
Advanced Techniques in Biology & Medicine
Arika, W. M., Ogola, P. E., Nyamai, D. W., Mawia, A. M., Wambua, F. K., Kiboi, N. G., Wambani, J. R., Njagi, S. M., Rachuonyo, H. O., Emmah, K. O., et al. (2018) · Advanced Techniques in Biology & Medicine · doi:10.4172/2379-1764 · Cited by 35
Clinical predictors of postoperative hemoglobin drift
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Molecular mechanisms of hepcidin regulation in sea bass (Dicentrarchus labrax)
Neves, J. V., Caldas, C., Wilson, J. M., & Rodrigues, P. (2011) · Fish & Shellfish Immunology · doi:10.1016/j.fsi.2011.10.006 · Cited by 38
Genetic factors influencing hemoglobin levels in 15,567 blood donors: results from the Danish Blood Donor Study
Sørensen, E., Rigas, A. S., Didriksen, M., Burgdorf, K. S., Thørner, L. W., Pedersen, O. B., Hjalgrim, H., Petersen, M. S., Erikstrup, C., & Ullum, H. (2018) · Transfusion · doi:10.1111/trf.15075 · Cited by 35
“As described in the introduction, the TMPRSS6 plays a role in regulating hepcidin synthesis.(14) An overexpression of TMPRSS6 may result in iron overload because of blockage of different pathways for upregulation of hepcidin,(8,15) and it has been suggested that mutational inactivation of the TMPRSS6 reduces the level…”
Background
The benefits of iron supplementation following blood donation vary with baseline iron status
Mast, A. E., Szabó, A., Stone, M., Cable, R. G., Spencer, B. R., Kiss, J. E., & (REDS)‐III, F. T. N. R. E. D. E. S. (2020) · American Journal of Hematology · doi:10.1002/ajh.25800 · Cited by 40
“Iron deficiency, anemia, and increased erythropoietic activity are all associated with whole blood donation and with decreased plasma hepcidin.(25,26) Accordingly, plasma hepcidin decreased following whole blood donation in all donors.”
Background
Cloning, characterization and tissue-specific expression of the antimicrobial peptide hepcidin from caspian trout (Salmo caspius) and the antibacterial activity of the synthetic peptide
Shirdel, I., Kalbassi, M. R., Hosseinkhani, S., Paknejad, H., & Wink, M. (2019) · Fish & Shellfish Immunology · doi:10.1016/j.fsi.2019.05.010 · Cited by 35
MASL1 induces erythroid differentiation in human erythropoietin-dependent CD34+ cells through the Raf/MEK/ERK pathway
Kumkhaek, C., Aerbajinai, W., Liu, W., Zhu, J., Uchida, N., Kurlander, R. J., Hsieh, M. M., Tisdale, J. F., & Rodgers, G. P. (2013) · Blood · doi:10.1182/blood-2011-10-385252 · Cited by 33
“IL-6 induces an upregulation of hepcidin expression, which inhibits iron export from macrophages by binding to the iron exporter ferroportin and inducing its degradation, thereby blocking availability of iron for erythropoiesis.(46) A study has demonstrated that downregulated MASL1 expression in macrophages strongly e…”
Background
Association of mitochondrial iron deficiency and dysfunction with idiopathic restless legs syndrome
Haschka, D., Volani, C., Stefani, A., Tymoszuk, P., Mitterling, T., Holzknecht, E., Heidbreder, A., Coassin, S., Sumbalová, Z., Seifert, M., et al. (2018) · Movement Disorders · doi:10.1002/mds.27482 · Cited by 36
“757 Ferritin (μg/L), median (range) 81 (10-415) 97 (7-713) 0.”
Influential
Maternal iron homeostasis: effect on placental development and function
Roberts, H., Bourque, S. L., & Renaud, S. J. (2020) · Reproduction · doi:10.1530/rep-20-0271 · Cited by 36
“The regulation of iron availability during pregnancy is dependent on hepcidin, a hormone produced mainly by hepatocytes that controls levels of circulating iron (Nemeth & Ganz 2006).”
Background
Meta-analysis of Zn, Cu and Fe in the hair of Chinese children with recurrent respiratory tract infection
Mao, S., Zhang, A., & Huang, S. (2014) · Scandinavian Journal of Clinical and Laboratory Investigation · doi:10.3109/00365513.2014.921323 · Cited by 35
Long-term risk of type 2 diabetes in relation to habitual iron intake in women with a history of gestational diabetes: a prospective cohort study
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“Note that iron absorption is regulated by complex genetic regulatory mechanisms including homeostatic hormones such as hepcidin (47).”
Background
The role of STAT, AP-1, E-box and TIEG motifs in the regulation of hepcidin by IL-6 and BMP-9: Lessons from human HAMP and murine Hamp1 and Hamp2 gene promoters
Truksa, J., Lee, P. L., & Beutler, E. (2007) · Blood Cells Molecules and Diseases · doi:10.1016/j.bcmd.2007.06.014 · Cited by 33
“Hepcidin is a principal regulator of iron metabolism affecting iron uptake from intestine and release of iron from body stores in liver and macrophages [1].”
Background
BMPER Protein Is a Negative Regulator of Hepcidin and Is Up-regulated in Hypotransferrinemic Mice
Patel, N., Masaratana, P., Díaz‐Castro, J., Latunde-Dada, G. O., Qureshi, A., Lockyer, P. P., Jacob, M., Arno, M. J., Matak, P., Mitry, R. R., et al. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.310789 · Cited by 33
Ferroportin-1 is a ‘nuclear'-negative acute-phase protein in rat liver: a comparison with other iron-transport proteins
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Glucose abnormalities in non‐alcoholic fatty liver disease and chronic hepatitis C virus infection: the role of iron overload
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“of both intestinal iron absorption and reticuloendothelial iron release [87].”
Background
Copper proteins and ferroxidases in human plasma and that of wild-type and ceruloplasmin knockout mice
Gray, L. W., Kidane, T. Z., Nguyen, A., Akagi, S., Petrasek, K., Chu, Y.-L., Cabrera, A., Kantardjieff, K. A., Mason, A. Z., & Linder, M. C. (2008) · Biochemical Journal · doi:10.1042/bj20081983 · Cited by 33
Iron status in obesity: An independent association with metabolic parameters and effect of weight loss
Guglielmi, V., D’Adamo, M., Bellia, A., Ciotto, R. T., Federici, M., Lauro, D., & Sbraccia, P. (2015) · Nutrition Metabolism and Cardiovascular Diseases · doi:10.1016/j.numecd.2015.02.012 · Cited by 32
“Hepcidin, which is produced mainly by the liver and to a lesser extent in the adipose tissue, controls the flux of iron into plasma by triggering the iron exporter ferroportin degradation, and thus it increases iron sequestration within intestinal enterocytes, hepatocytes, and ironrecycling macrophages [18].”
Background
Treatment with anti-IL-6 receptor antibody prevented increase in serum hepcidin levels and improved anemia in mice inoculated with IL-6–producing lung carcinoma cells
Noguchi‐Sasaki, M., Sasaki, Y., Shimonaka, Y., Mori, K., & Fujimoto-Ouchi, K. (2016) · BMC Cancer · doi:10.1186/s12885-016-2305-2 · Cited by 32
“Hepcidin is a 25-amino acid peptide hormone produced mainly in the liver that regulates intestinal iron absorption by causing degradation of the enterocyte iron transporter ferroportin, iron recycling by macrophages, and iron release from hepatic stores [4, 6].”
Administration of dietary recombinant hepcidin on grass carp (Ctenopharyngodon idella) against Flavobacterium columnare infection under cage aquaculture conditions
Chen, T., Zhou, J., Qu, Z.-L., Zou, Q., Liu, X., Su, J., Fu, X., & Yuan, G. (2020) · Fish & Shellfish Immunology · doi:10.1016/j.fsi.2020.01.042 · Cited by 32
IL-1β Drives Production of FGF-23 at the Onset of Chronic Kidney Disease in Mice
McKnight, Q., Jenkins, S., Li, X., Nelson, T., Marlier, A., Cantley, L. G., Finberg, K. E., & Fretz, J. A. (2020) · Journal of Bone and Mineral Research · doi:10.1002/jbmr.4003 · Cited by 32
“IL-1β production from the kidney correlates with FGF-23 expression Having demonstrated that neither altered PTH/phosphate/1,25 (OH)2D3 nor anemia correlate with circulating iFGF-23 in early CKD, we next investigated for the presence of several inflammatory proteins that are known to be upregulated during CKD and have…”
BackgroundMethodInfluential
The efficacy and safety of roxadustat for anemia in patients with chronic kidney disease: a meta-analysis
Zheng, Q., Yang, H., Fu, X., Huang, Y., Wei, R., Wang, Y., Liu, Y., & Liu, W. J. (2020) · Nephrology Dialysis Transplantation · doi:10.1093/ndt/gfaa110 · Cited by 34
Signaling Integration of Hydrogen Sulfide and Iron on Cellular Functions
Arif, H. M., Qian, Z., & Wang, R. (2021) · Antioxidants and Redox Signaling · doi:10.1089/ars.2021.0203 · Cited by 33
“Color images are available online. of hepcidin may lead to iron deﬁciency (113).”
The iron regulatory hormone hepcidin inhibits expression of iron release as well as iron uptake proteins in J774 cells
Du, F., Qian, Z., Gong, Q., Zhu, Z. J., Lü, L., & Ke, Y. (2012) · The Journal of Nutritional Biochemistry · doi:10.1016/j.jnutbio.2011.12.002 · Cited by 33
“Accumulateddatahave indicated that hepcidin is theprincipal regulator in the maintenance of systemic iron homeostasis [10,11].”
Background
Co-Administration of Iron and a Bioavailable Curcumin Supplement Increases Serum BDNF Levels in Healthy Adults
Lorinczova, H. T., Fitzsimons, O., Mursaleen, L., Renshaw, D. W., Begum, G., & Zariwala, M. G. (2020) · Antioxidants · doi:10.3390/antiox9080645 · Cited by 32
“Hepcidin is the key regulatory protein of systemic iron homeostasis and protects against iron overload [89].”
Background
Host–Pathogen Interactions of Marine Gram-Positive Bacteria
Gnanagobal, H., & Santander, J. (2022) · Biology · doi:10.3390/biology11091316 · Cited by 36
Effect of ferroportin polymorphism on iron homeostasis and infection
Kasvosve, I. (2012) · Clinica Chimica Acta · doi:10.1016/j.cca.2012.11.013 · Cited by 34
A comparison of ceruloplasmin to biological polyanions in promoting the oxidation of Fe2+ under physiologically relevant conditions
Wong, B. X. W., Ayton, S., Lam, L. Q., Lei, P., Adlard, P. A., Bush, A. I., & Duce, J. A. (2014) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/j.bbagen.2014.08.006 · Cited by 32
Transition metals at the host–pathogen interface: howNeisseriaexploit human metalloproteins for acquiring iron and zinc
Neumann, W., Hadley, R. C., & Nolan, E. M. (2017) · Essays in Biochemistry · doi:10.1042/ebc20160084 · Cited by 30
“During infection, the human host further lowers iron availability at sites of infection by deploying iron-sequestering host-defense proteins such as lactoferrin (LF) and lipocalin-2 [34,35], and increasing production of the peptide hormone hepcidin to inhibit iron transport into the bloodstream [36].”
Background
Impairment of Hepcidin Upregulation by Lipopolysaccharide in the Interleukin-6 Knockout Mouse Brain
Zhang, F., Hou, H., Yin, Z., Chang, L. Y., Li, F., Chen, Y.-J., Ke, Y., & Qian, Z. (2017) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2017.00367 · Cited by 32
“In the periphery, it has been well-documented that hepcidin plays a central role in maintaining normal iron homeostasis by controlling the expression of iron transport proteins in the intestine, liver, spleen and bone marrow (Hentze et al., 2004; Nemeth and Ganz, 2006).”
Background
Factors affecting iron absorption and the role of fortification in enhancing iron levels
Perera, D. N., Palliyaguruge, C. L., Eapasinghe, D. D., Maleesha, L. D., Seneviratne, R. A. C. H., Demini, S. M. D., Jayasinghe, J. A. S. M., Faizan, M., Rajagopalan, U., Galhena, B. P., et al. (2023) · Nutrition Bulletin · doi:10.1111/nbu.12643 · Cited by 39
Leishmania infection triggers hepcidin‐mediated proteasomal degradation of Nramp1 to increase phagolysosomal iron availability
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“It is worth noting that in the infected macrophages, hepcidin was found to be mostly distributed in vesicular compartments suggesting that it may have important intracellular role(s) in addition to its well-known paracrine action (Figure S7b) (Nemeth & Ganz, 2006).”
Background
Prevalence of Iron Deficiency and its Sociodemographic Patterning in Indian Children and Adolescents: Findings from the Comprehensive National Nutrition Survey 2016–18
Kulkarni, B., Peter, R., Ghosh, S., Pullakhandam, R., Thomas, T. S., Reddy, G. B., Rajkumar, H., Kapil, U., Deb, S., JOHNSTON, R. V., et al. (2021) · Journal of Nutrition · doi:10.1093/jn/nxab145 · Cited by 30
Effect of fluvastatin on serum prohepcidin levels in patients with end-stage renal disease
Arabul, M., Güllülü, M., Yilmaz, Y. N., Akdağ, İ., Kahvecioğlu, S., Eren, M. A., & Dilek, K. (2008) · Clinical Biochemistry · doi:10.1016/j.clinbiochem.2008.05.010 · Cited by 30
Mutation of the gastric hydrogen-potassium ATPase alpha subunit causes iron-deficiency anemia in mice
Krieg, L., Milstein, O., Krebs, P., Xia, Y., Beutler, B., & Du, X. (2011) · Blood · doi:10.1182/blood-2011-04-350082 · Cited by 30

Authors: Nemeth, E., & Ganz, T.
Affiliations: University of California, Los Angeles (US)
ORCID: Nemeth, Elizabeta
Ganz, Tomas
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
DOI: 10.1146/annurev.nutr.26.061505.111303
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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Regulation of Iron Metabolism by Hepcidin

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