Hepcidin: The Master Regulator of Iron Homeostasis
Hepcidin is a 25-amino acid peptide hormone primarily synthesized by hepatocytes that serves as the key regulator of systemic iron homeostasis by binding to ferroportin and blocking cellular iron export, thereby controlling iron absorption, recycling, and mobilization. 1
Structure and Production
- Hepcidin is encoded by the HAMP gene located on chromosome 19, which initially produces an 84-amino acid pre-prohepcidin that undergoes post-translational processing to form the mature 25-amino acid peptide 1
- While predominantly produced in the liver, hepcidin is also synthesized in smaller amounts by macrophages, adipocytes, and cardiac tissue 1
- Hepcidin is excreted by the kidneys, with impaired excretion in chronic kidney disease contributing to iron dysregulation 1
Mechanism of Action
- Hepcidin binds to ferroportin, the sole cellular iron exporter found on enterocytes, macrophages, and hepatocytes, causing its internalization and degradation 1, 2
- This binding blocks iron export from cells into the bloodstream, effectively:
- The net effect is a reduction in serum iron levels when hepcidin is elevated 1, 4
Regulation of Hepcidin Production
Hepcidin synthesis is controlled by multiple physiologic and pathologic factors:
Factors that increase hepcidin production:
- Iron excess (high transferrin saturation and iron stores) 1, 3
- Inflammation (via IL-6 and the JAK/STAT3 pathway) 1, 5
- Infection (part of innate immunity) 2, 5
Factors that decrease hepcidin production:
- Iron deficiency 1, 6
- Enhanced erythropoiesis 1
- Hypoxia 1, 3
- Erythropoietin administration 1
- Chronic liver disease (impaired hepatic synthesis) 1
- Sex hormones (testosterone and estrogen) 1
Molecular Signaling Pathways
- The BMP/SMAD pathway is the main regulator of hepcidin transcription 1
- BMP2 maintains basal hepcidin transcription
- BMP6 upregulates hepcidin in response to iron overload
- Both are produced by liver sinusoidal endothelial cells 1
- Efficient iron signaling requires co-receptors including:
- Hemojuvelin (HJV)
- Hemochromatosis protein (HFE)
- Transferrin receptor 2 (TfR2) 1
- Inflammation triggers hepcidin production through:
- IL-6 activating the JAK/STAT3 pathway
- Activin B stimulating the BMP/SMAD pathway 1
Role in Disease States
Iron Overload Conditions
- Hereditary hemochromatosis: Caused by hepcidin deficiency due to mutations in HFE, HJV, or other regulatory genes 1, 6
- Iron-loading anemias (e.g., β-thalassemia): Associated with inappropriate hepcidin suppression leading to increased iron absorption 3, 6
Iron Restriction Conditions
- Anemia of inflammation: Characterized by hepcidin excess, limiting iron availability for erythropoiesis 4, 5
- Iron-refractory iron deficiency anemia: Results from pathologically elevated hepcidin levels 3, 4
- Anemia of chronic kidney disease: Involves decreased hepcidin excretion and increased production 1, 4
Role in Host Defense
- Hepcidin's ability to restrict serum iron is an important host defense mechanism against iron-dependent pathogens 2, 5
- Particularly relevant in infections with siderophilic pathogens like Vibrio vulnificus, where hepcidin-mediated hypoferremia helps limit bacterial growth 2
- Patients with hemochromatosis (hepcidin deficiency) have increased susceptibility to certain infections due to higher circulating iron levels 2
Therapeutic Implications
- Hepcidin agonists and inducers are being developed for treating iron overload disorders 6
- Hepcidin antagonists and inhibitors may help treat anemias characterized by hepcidin excess 6, 7
- Measurement of hepcidin levels may provide diagnostic value in screening and monitoring iron disorders 1, 7
Hepcidin's central role in iron metabolism makes it a critical target for both diagnostic applications and therapeutic interventions in various iron disorders 3, 6.