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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Do high blood hepcidin concentrations contribute to low ferritin levels in young tennis players at the end of tournament season?
Ziemann, E., Kasprowicz, K., Kasperska, A., Zembroń-Łacny, A., Antosiewicz, J., & Laskowski, R. (2013) · Europe PMC (PubMed Central) · Cited by 20
Hepcidin Decreases Rotenone-Induced α-Synuclein Accumulation via Autophagy in SH-SY5Y Cells
Li, M., Hu, J., Yuan, X., Shen, L., Zhu, L., & Luo, Q. (2020) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2020.560891 · Cited by 20
“Hepcidin is a liver-secreted hormone that plays a critical role in iron homeostasis in the peripheral and central nervous systems (Park et al., 2001; Nemeth and Ganz, 2006; Zechel et al., 2006).”
Background
Phylogenetic and Ontogenetic View of Erythroblastic Islands
Giger, K. M., & Kalfa, T. A. (2015) · BioMed Research International · doi:10.1155/2015/873628 · Cited by 20
Intake of Alcoholic Beverages Is a Predictor of Iron Status and Hemoglobin in Adult Tanzanians ,
Malenganisho, W. L. M., Magnussen, P., Vennervald, B. J., Krarup, H. B., Kæstel, P., Siza, J. E., Kaatano, G. M., Temu, M. M., & Friis, H. (2007) · Journal of Nutrition · doi:10.1093/jn/137.9.2140 · Cited by 20
“This results in sequestration of iron in the stores and iron-limited erythropoiesis and eventually anemia of inflammation (38).”
Determinants of hepcidin levels in sepsis-associated acute kidney injury: Impact on pAKT/PTEN pathways?
Schaalan, M. F., & Mohamed, W. A. (2016) · Journal of Immunotoxicology · doi:10.1080/1547691x.2016.1183733 · Cited by 20
“Nemeth and Ganz (2006) previously investigated the regulatory pattern of HEPC and reported that the regulation of HEPC expression in the liver occurred at the transcriptional level and was modulated by iron status, inflammation and hypoxia.”
Background
PCB-77 disturbs iron homeostasis through regulating hepcidin gene expression
Wang, L., Zhang, S., Lin, R., Li, L., Zhang, D., Li, X., & Liu, S. (2013) · Gene · doi:10.1016/j.gene.2013.09.023 · Cited by 19
“, 2006) and even cancers (Bystrom et al., 2012; Nemeth and Ganz, 2006).”
Background
Bacteria from the gut influence the host micronutrient status
Kouadio, D. K. D., Wieringa, F. T., Greffeuille, V., & Humblot, C. (2023) · Critical Reviews in Food Science and Nutrition · doi:10.1080/10408398.2023.2227888 · Cited by 19
“Iron homeostasis is regulated by the hormone hepcidin, which inhibits the release of iron into the plasma through different mechanisms (Nemeth and Ganz 2006).”
Impact of baseline serum ferritin and supplemental iron on altitude‐induced hemoglobin mass response in elite athletes
Koivisto, A., Svendsen, I. S., Skattebo, Ø., Hallén, J., & Paulsen, G. (2021) · Scandinavian Journal of Medicine and Science in Sports · doi:10.1111/sms.13982 · Cited by 19
Identification and characterization of hepcidin from Nile Tilapia (Oreochromis niloticus) in response to bacterial infection and iron overload
Yin, X., Chen, N., Mu, L., Bai, H., Wu, H., Qi, W., Huang, Y., Jian, J., Wang, A., & Ye, J. (2021) · Aquaculture · doi:10.1016/j.aquaculture.2021.737317 · Cited by 20
Large-scale staple food fortification as a complementary strategy to address vitamin and mineral vulnerabilities in India: A critical review
Duggal, M., Sesikeran, B., Arlappa, N., Nair, S., Shekhar, V., & Sabharwal, V. (2022) · Indian Journal of Public Health · doi:10.4103/ijph.ijph_708_22 · Cited by 19
Effects of Oral Iron Supplementation on Blood Iron Status in Athletes: A Systematic Review, Meta-Analysis and Meta-Regression of Randomized Controlled Trials
Šmid, A. N., Golja, P., Hadžić, V., Abazović, E., Drole, K., & Paravlic, A. H. (2024) · Sports Medicine · doi:10.1007/s40279-024-01992-8 · Cited by 27
“It has also been reported that higher dosages of iron intake result in diminished fractional iron absorption within the 24 h following ingestion [24–26], although the absolute absorption may actually be enhanced.”
BackgroundInfluential
Iron-Refractory Iron Deficiency Anemia
Keskin, E. Y., & Yenicesu, İ. (2015) · Turkish Journal of Hematology · doi:10.4274/tjh.2014.0288 · Cited by 21
“In cases of iron loading, hepcidin expression is induced to inhibit intestinal iron uptake, whereas iron deficiency results in reduced hepcidin expression to increase the availability of iron for erythropoiesis [33,34].”
Background
Efficacy of intravenous iron treatment for chemotherapy-induced anemia: A prospective Phase II pilot clinical trial in South Korea
Jang, J. H., Kim, Y., Park, S., Kım, K., Kim, S. J., Kim, W. S., Jung, C. W., Lee, J., & Lee, S. (2020) · PLoS Medicine · doi:10.1371/journal.pmed.1003091 · Cited by 20
“The measurement of hepcidin may be a useful addition to the differential diagnosis of tumorrelated ACD and IDA, thereby guiding corrective treatment.”
BackgroundInfluential
Hepcidin treatment in Hfe−/− mice diminishes plasma iron without affecting erythropoiesis
Morán‐Jiménez, M., Méndez, M., Santiago, B., Rodríguez‐García, M. E., Moreno‐Carralero, M., Sánchez‐Lucío, A., Grau, M., & de Salamanca, R. E. (2010) · European Journal of Clinical Investigation · doi:10.1111/j.1365-2362.2010.02291.x · Cited by 19
Long-Term Exposure to Cadmium Causes Hepatic Iron Deficiency through the Suppression of Iron-Transport-Related Gene Expression in the Proximal Duodenum
Tokumoto, M., Lee, J.-Y., Fujiwara, Y., & Satoh, M. (2023) · Toxics · doi:10.3390/toxics11070641 · Cited by 18
“When blood iron is in excess, Hamp is produced and Fpn1 is degraded, thereby regulating the iron delivered into the blood [20,21].”
Background
Malaria exacerbates inflammation‐associated elevation in ferritin and soluble transferrin receptor with only modest effects on iron deficiency and iron deficiency anaemia among rural Zambian children
Barffour, M. A., Schulze, K. J., Coles, C. L., Chileshe, J., Kalungwana, N., Siamusantu, W., Arguello, M. A., Moss, W. J., West, K. P., & Palmer, A. (2017) · Tropical Medicine & International Health · doi:10.1111/tmi.13004 · Cited by 19
Iron Deficiency and Deranged Myocardial Energetics in Heart Failure
Tkaczyszyn, M., Górniak, K. M., Lis, W., Ponikowski, P. P., & Jankowska, E. A. (2022) · International Journal of Environmental Research and Public Health · doi:10.3390/ijerph192417000 · Cited by 19
“The human body cannot actively remove excessive iron in case of overload and therefore iron absorption is tightly controlled, in particular through the effects of hepatic peptide hormone hepcidin [62,65,74].”
Background
Suppressed cytokine production in whole blood cultures may be related to iron status and hepcidin and is partially corrected following weight reduction in morbidly obese pre-menopausal women
Tussing-Humphreys, L. M., Pini, M., Ponemone, V., Braunschweig, C. L., & Fantuzzi, G. (2010) · Cytokine · doi:10.1016/j.cyto.2010.11.008 · Cited by 19
“Hepcidin is an anti-microbial peptide involved in innate immunity and is the body’s main regulator of systemic iron homeostasis [22,23].”
Background
Iron availability and oxygen tension regulate the Yersinia Ysc type III secretion system to enable disseminated infection
Hooker-Romero, D., Mettert, E. L., Schwiesow, L., Balderas, D., Alvarez, P. A., Kicin, A., Gonzalez, A. L., Plano, G. V., Kiley, P. J., & Auerbuch, V. (2019) · PLoS Pathogens · doi:10.1371/journal.ppat.1008001 · Cited by 18
“The importance of nutritional immunity is exemplified by the increased susceptibility of individuals with iron overload, including β-thalassemia, sideroblastic anemia, and hemochromatosis, to systemic infections with pathogenic Yersinia, Vibrio parahaemolyticus, and several other pathogens [6, 7].”
Background
Total Synthesis of Human Hepcidin through Regioselective Disulfide‐Bond Formation by using the Safety‐Catch Cysteine Protecting Group 4,4′‐Dimethylsulfinylbenzhydryl
Dekan, Z., Mobli, M., Pennington, M. W., Fung, E., Nemeth, E., & Alewood, P. F. (2014) · Angewandte Chemie · doi:10.1002/ange.201310103 · Cited by 18
Self-citation
Pre-operative anaemia in colon cancer patients became normal after more than a year post-operatively but did not influence oncological outcome in the final analysis
Fjørtoft, I., Furnes, B., Hausken, T., Storli, K. E., Eide, G. E., & Søndenaa, K. (2013) · Scandinavian Journal of Gastroenterology · doi:10.3109/00365521.2013.781216 · Cited by 18
“An increased plasma level of hepcidin inhibits intestinal iron uptake and iron release from stores [30].”
Background
Iron
Ponka, P., Tenenbein, M., & Eaton, J. W. (2014) · Elsevier eBooks · doi:10.1016/b978-0-444-59453-2.00041-x · Cited by 20
Iron acquisition by Mycobacterium tuberculosis residing within myeloid dendritic cells
Olakanmi, O., Kesavalu, B., Abdalla, M. Y., & Britigan, B. E. (2013) · Microbial Pathogenesis · doi:10.1016/j.micpath.2013.09.002 · Cited by 17
Silkworm feces extract improves iron deficiency anemia via suppressing hepcidin expression and promoting iron-regulatory proteins expression
Huang, X. B., Wu, J., Li, Q., Gu, S., Chen, Z., & Wang, K. (2017) · RSC Advances · doi:10.1039/c7ra09576g · Cited by 17
Increased serum hepcidin levels in patients with porphyria cutanea tarda
Darwich, E., To‐Figueras, J., Molina‐López, R. A., Deulofeu, R., Olbina, G., Westerman, M., Sánchez-Tapias, J., Muñoz‐Santos, C., & Herrero, C. (2012) · Journal of the European Academy of Dermatology and Venereology · doi:10.1111/j.1468-3083.2012.04511.x · Cited by 17
Might the beneficial effects of statin drugs be related to their action on iron metabolism?
Mascitelli, L., & Goldstein, M. R. (2012) · QJM · doi:10.1093/qjmed/hcs204 · Cited by 17
Subcutaneous Adipose Tissue from Obese and Lean Adults Does Not Release HepcidinIn Vivo
Tussing-Humphreys, L. M., Frayn, K. N., Smith, S. R., Westerman, M. E., Dennis, A., Nemeth, E., Thomson, J. L., & Pusatcioglu, C. K. (2011) · The Scientific World JOURNAL · doi:10.1100/2011/634861 · Cited by 19
“When hepcidin binds to Fpn, the two proteins are internalized and degraded within lysosomes [3].”
BackgroundSelf-citation
Duodenal Absorption and Tissue Utilization of Dietary Heme and Nonheme Iron Differ in Rats
Cao, C. Q., Thomas, C. E., Insogna, K. L., & O'Brien, K. O. (2014) · Journal of Nutrition · doi:10.3945/jn.114.197939 · Cited by 19
“The absorption of nonheme iron is tightly controlled by body iron status and the liver-derived peptide hormone hepcidin (2).”
Background
Iron storage disease (hemochromatosis) and hepcidin response to iron load in two species of pteropodid fruit bats relative to the common vampire bat
Stasiak, I. M., Smith, D. A., Ganz, T., Crawshaw, G. J., Hammermueller, J., Bienzle, D., & Lillie, B. N. (2018) · Journal of Comparative Physiology B · doi:10.1007/s00360-018-1155-4 · Cited by 17
Self-citation
The role of heparin, heparanase and heparan sulfates in hepcidin regulation
Asperti, M., Denardo, A., Gryzik, M., Arosio, P., & Poli, M. (2019) · Vitamins and hormones · doi:10.1016/bs.vh.2019.01.008 · Cited by 17
Iron Deficiency and Neuroendocrine Regulators of Basal Metabolism, Body Composition and Energy Expenditure in Rats
Moreno‐Fernández, J., Díaz‐Castro, J., Alférez, M. J. M., & López‐Aliaga, I. (2019) · Nutrients · doi:10.3390/nu11030631 · Cited by 18
“Hepcidin also controls the Fe levels directly acting reciprocally with the FPN1, driving to the internalization and degradation of FPN1 when levels of Fe are high, consequently blocking the liberation of the Fe in the sites of storage: hepatocytes, enterocytes and macrophages [24].”
Background
Long-term Effect of Split Iron Dextran/Hemoglobin Supplementation on Erythrocyte and Iron Status, Growth Performance, Carcass Parameters, and Meat Quality of Polish Large White and 990 Line Pigs
Szudzik, M., Lipiński, P., Jończy, A., Mazgaj, R., Pieszka, M., Kamyczek, M., Smuda, E., & Starzyński, R. R. (2019) · Biological Trace Element Research · doi:10.1007/s12011-019-01950-w · Cited by 17
Hepatitis C virus core+1/ARF protein decreases hepcidin transcription through an AP1 binding site
Kotta‐Loizou, I., Vassilaki, N., Pissas, G., Kakkanas, A., Bakiri, L., Bartenschlager, R. F. W., & Mavromara, P. (2013) · Journal of General Virology · doi:10.1099/vir.0.050328-0 · Cited by 17
“Reduced levels of hepcidin, a key negative regulator of iron absorption (Nemeth & Ganz, 2006; Roy et al., 2007), have been linked to iron accumulation in HCV patients (Nagashima et al., 2006; Fujita et al., 2007; Nishina et al., 2008).”
Background
Iron supplementation in mouse expands cellular innate defences in spleen and defers lethal malaria infection
Azcárate, I. G., Sánchez-Jaut, S., Marín-García, P., Linares, M., Pérez-Benavente, S., García-Sánchez, M., Uceda, J., Kamali, A. N., Morán-Jiménez, M.-J., Puyet, A., et al. (2017) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2017.09.027 · Cited by 12
“As we could expect from a physiological response to iron overload and inflammation [42, 43], the expression of hepatic hepcidin was upregulated.”
Background
Does moderate iron deficiency protect against childhood illness? A test of the optimal iron hypothesis in Tanzania
Hadley, C., & DeCaro, J. A. (2015) · American Journal of Physical Anthropology · doi:10.1002/ajpa.22756 · Cited by 17
Chimeric Protein IPath® with Chelating Activity Improves Atlantic Salmon’s Immunity against Infectious Diseases
Valenzuela‐Muñoz, V., Benavente, B. P., Casuso, A., Leal, Y., & Gallardo‐Escárate, C. (2021) · Vaccines · doi:10.3390/vaccines9040361 · Cited by 16
“Among them, hepcidin plays a pivotal role in the regulation of iron homeostasis, fulfilling roles in the regulation of iron concentrations in plasma, tissue distribution of iron in the intestine, iron storage in the liver, and iron recycling by macrophages [44,45].”
Background
Growth-promoting effect of antimicrobial peptide Scy-hepc on mariculture large yellow croaker Larimichthys crocea and the underlying mechanism.
An, Z., Chen, F.-Y., Hao, H., Xiong, M., Peng, H., Sun, H., & Wang, K.-J. (2023) · Fish and Shellfish Immunology · doi:10.1016/j.fsi.2023.108649 · Cited by 14
Pentosan polysulfate to control hepcidin expression in vitro and in vivo
Asperti, M., Denardo, A., Gryzik, M., Castagna, A., Girelli, D., Naggi, A., Arosio, P., & Poli, M. (2020) · Biochemical Pharmacology · doi:10.1016/j.bcp.2020.113867 · Cited by 16
Treatment of Renal Anemia in Patients With Hemodialysis Using Hypoxia-inducible Factor (HIF) Stabilizer, Roxadustat: A Short-term Clinical Study
Mima, A., & Horii, Y. (2022) · In Vivo · doi:10.21873/invivo.12892 · Cited by 16
Effect of alcohol exposure on hepatic superoxide generation and hepcidin expression
Harrison-Findik, D. D., Lu, S., Zmijewski, E. M., Jones, J., & Zimmerman, M. C. (2013) · World Journal of Biological Chemistry · doi:10.4331/wjbc.v4.i4.119 · Cited by 16
Iron-deficiency anemia secondary to mutations in genes controlling hepcidin
Cau, M., Melis, M. A., Congiu, R., & Galanello, R. (2010) · Expert Review of Hematology · doi:10.1586/ehm.10.2 · Cited by 16

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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