From the Guidelines
Hepcidin plays a crucial role in iron sensing and signaling pathways as the master regulator of iron homeostasis in the body, controlling both iron absorption from the intestine and iron release from storage sites.
Key Points
- Hepcidin is a 25-amino acid peptide hormone that is predominantly synthesized by hepatocytes and excreted by the kidneys, as noted in the study by 1.
- The synthesis of hepcidin is controlled by certain physiologic and pathologic triggers that reflect circulating and stored iron levels, erythropoietic activity, hypoxia, and innate immune signaling, as discussed in 1.
- Hepcidin binds to ferroportin to block cellular iron export, both by occluding the export channel and by inducing its degradation, thereby limiting iron release to the plasma from macrophages and duodenal enterocytes, as explained in 1 and further supported by 1 and 1.
- Conditions with hepcidin excess, such as inflammation, cause iron-restricted anemia, while hepcidin deficiency, as seen in hereditary hemochromatosis, leads to iron overload, as understood from the mechanisms described in 1, 1, and 1.
Mechanism of Action
- When iron levels are high, the BMP-SMAD pathway is activated, leading to increased hepcidin transcription, as noted in the example answer.
- Inflammation also increases hepcidin through the IL-6/JAK2/STAT3 pathway, while erythropoietic activity suppresses it via erythroferrone, as discussed in the example answer and supported by the studies 1 and 1.
- Once secreted, hepcidin binds to ferroportin, causing its internalization and degradation, thereby blocking iron release into circulation, as explained in the example answer and the studies 1, 1, and 1.
Clinical Implications
- Understanding the role of hepcidin in iron homeostasis has led to therapeutic approaches targeting hepcidin for treating iron disorders, as mentioned in the example answer and supported by the studies 1, 1, and 1.
- The regulation of hepcidin is crucial in conditions such as hereditary hemochromatosis and iron-refractory iron deficiency anemia, as discussed in 1.
- The study by 1 highlights the importance of hepcidin in the pathophysiology of cancer-related anemia and the potential for therapeutic interventions targeting hepcidin in this context.
From the Research
Role of Hepcidin in Iron Sensing and Signaling Pathways
- Hepcidin is a peptide hormone synthesized by hepatocytes that plays a crucial role in regulating systemic iron homeostasis 2, 3, 4.
- It controls dietary iron absorption and iron egress out of iron storage cells, and induces iron redistribution in various organs 3, 4.
- Hepcidin exerts its effects through its receptor, the cellular iron exporter ferroportin, and its production is stimulated by plasma iron and iron stores 2, 4.
- Important regulators of hepcidin include plasma iron concentrations, body iron stores, infection and inflammation, and erythropoiesis 2, 4.
Signaling Pathways Regulating Hepcidin
- Hepcidin is regulated by a number of physiological stimuli and their associated signaling pathways, including inflammation and erythropoietic activity 5, 4.
- The signaling pathways and molecules involved in hepcidin modulation ultimately contribute to the regulation of systemic or local iron homeostasis 5.
- Erythroferrone, a hormone produced by erythropoietin-stimulated erythroblasts, suppresses hepcidin production, leading to increased iron absorption and release of iron from stores 4.
Hepcidin in Iron Overload Disorders
- Hepcidin deficiency or alterations in its target, ferroportin, can result in dysregulated iron absorption, tissue maldistribution of iron, and iron overload 6.
- Hepcidin deficiency has been reported in hereditary hemochromatosis and attributed to mutations in HFE, transferrin receptor 2, hemojuvelin, and the hepcidin gene itself 6.
- Hepcidin is also suppressed in patients with thalassemia syndromes and congenital dyserythropoietic anemia type 1, and is undetectable in patients with juvenile hemochromatosis with HAMP mutations 6.