CENTRAL ROLE OF HEPCIDIN

CENTRAL role of hepcidin

The study of Pigeon et al[1] revealed the first link between hepcidin and iron metabolism.  Hepcidin is the central regulatory molecule of systemic iron homeostasis and has a strong link to innate immunity.[2], prostate [3]

SYSTEMIC Iron Homeostasis and Hepcidin-25

Hepcidin is a 25 amino acid peptide (hepcidin-25),[4] also found in 2 smaller forms, i.e. hepcidin-20 and -22.5  The smaller forms of hepcidin do not elicit a hypoferremic response.5  No other identified biological functions of hepcidin-25, e.g. metal binding or host defense have been discovered.[5]  Hepcidin-25 is a circulating peptide hormone, primarily but not exclusively secreted by hepatocytes, in response to loading and inflammation. [6],[7]  The expression of hepcidin by hepatocytes is regulated by multiple signals.  Different regulatory inputs, e.g. hepatic iron stores, systemic iron availability, erythropoietic activity, hypoxia and infections/inflammation, are integrated transcriptionally2 i.e. expression of genes HFE, hemochromatosis type 2 (HFE2) and transferrin receptor 2 (TfR2).[8],[9]  Hepcidin regulates the entry of iron into plasma and decreases plasma iron by negative regulation of ferroportin.[10]  Internalization and degradation of ferroportin is induced by hepcidin.  The result is decreased dietary iron absorption, increased intracellular iron stores and decreased circulating iron concentrations.[11],[12],[13]

Hepcidin overproduction can lead to hypoferremia and the anaeamia of inflammation, whereas decreased hepcidin can lead to tissue iron overload.[14] To meet the body’s iron need, intestinal iron uptake, iron absorption, and mobilization from stores, is controlled by modulating hepcidin production. Hepcidin clearance is via the kidneys or by codegradation with ferroportin.

FERROPORTIN

The iron exporter ferroportin is presented at the basolateral surface of absorptive enterocytes of the duodenum, hepatocytes, placental cells and macrophages[15]  Hepcidin triggers ferroportin internalization and ubiquitination by forming a bond, leading to lysosomal degradation.  Ferroportin binds to the hepcidin-ferroportin complex phosphorylate ferroportin before internalization.[16]  Mammalian disorders of iron deficiency or overload may be caused by ferroportin dysfunction.

CELLULAR Iron Homeostasis

Similar tasks are involved in the maintenance of iron homeostasis by cells as at the systemic level.  Availability of appropriate supplies is assured to prevent toxicity.  Different mechanisms are at work as cellular iron traffic involves regulated iron excretion, in contrast to the systemic iron metabolism.

THREE interconnections have been identified between these two systems:

  1. The Ferroportin connection: Ferroportin 1 is subject to regulation by both systems.  The IRE/IRP system protects the cell iron exporting against detrimental iron losses.  Hepcidin protects the organism against systemic overload.
  2. The hypoxy- inducible factor (HIF2a) connection: HIF2a regulates divalent metal transporter-1 (DMT1) expression of duodenal enterocytes. Lack of HIF2a leads to decreased excretion of DMT1 and ferroportin leading to failure to promote iron absorption.[17]
  3. The TfR connection: Hepcidin expression is regulated by the signalling receptor TfR2[18],[19] and HFE “switch factor” that also binds to TfR1 competing with plasma Tf-Fe Hepcidin activation is affected by the equilibrium between the amount of plasma iron “sensing” TfR1 and “signalling” TfR2.  Hepcidin expression may be affected indirectly by IRP activity by regulating TfR1 levels in hepatocytes.

HEPCIDIN-MODULATING Agents

Different assay techniques are used to assess hepcidin concentrations, which make it difficult to interpret the result of the many reported studies.  Hepcidin is both a promising diagnostic tool and a therapeutic target for treating the spectrum of clinical disorders related to iron metabolism.[20]  Aberrant hepcidin production can be blamed for most disorders of iron balance.[21]  Hepcidin therapy is difficult to obtain in humans because the native peptide is difficult to produce in sufficient quantities.  Hepcidin modulating lipopolysaccharide-induction transcription suggests a role for hepcidin in modulating acute inflammatory responses to bacterial infection.[22]  Hepcidin may have local effects in tissues. Various cell types, other than hepatocytes, produce hepcidin and local hepcidin may prevent extracellular oxidative stress.  Hepcidin can also protect nearby cells from iron deficiency, deplete extracellular iron pools (that are available for extracellular pathogens) and affect inflammatory responses.[23],[24],[25]

HEPCIDIN Agonists and Antagonists

Hepcidin agonists and antagonists might be useful drug prospects in treating iron-related disorders.  Hepcidin deficiencies such as hereditary haemochromatosis (HH) (especially b-thalassaemias and other iron-loading anaemias) and acquired forms of nonhaemochromatotic iron-overload diseases could benefit from hepcidin agonists by preventing iron overload.  Patients suffering from diseases related to hepcidin excess such as iron-refractory iron deficiency anemia (IRIDA), anemia of chronic disease (ACD), multiple myeloma and other cancers, chronic kidney disease (CKD), cardiovascular disease and obesity-related iron deficiency, might benefit from hepcidin antagonists.[26],[27],[28]

HEPCIDIN Agonists

Clinical and pre-clinical studies reveal positive outcomes using synthetic hepcidin-25, bone morphogenetic protein (BMP) agonists, small hepcidin peptides and HIF stabilizers to prevent iron overload caused by hepcidin deficiency.[29],[30],[31] Transgenic hepcidin expression in HFE deprived mice can prevent iron overload.[32],[33],[34]  Iron overload induced by hepatitis C infection, b-thalassaemias and other iron-loading anaemias might be treated with small molecules to augment hepcidin synthesis/mimic its effects on ferroportin.[35]  HIF antagonists inhibit tumor angiogenesis in cancer cases and by blocking HIF could increase hepcidin concentrations in iron-overload diseases.

HEPCIDIN Antagonists

Clinical and pre-clinical studies reveal hepcidin expression can be decreased and iron abnormalities can be reversed by hepcidin antibodies, BMP antagonists and cytokine receptor antibodies.  Hepcidin expression can be decreased by HIF stabilizers, which can reverse iron abnormalities.[36],[37]  Using hepcidin antagonists for monitoring of the bioactive serum hepcidin appears to be complicated according to Xiao et al[38].  Several components interfere with the BMP/SMAD pathway.  Dorsomorphin (small inhibitor of BMP signaling) prevents hepcidin induction by iron in mice.[39]  Both twisted gastrulation protein (TWSG1)[40] and growth differentiation factor 15 (GDF15)[41],[42] can inhibit hepcidin expression in vitro and might have therapeutic potential.  Another antagonist of BMP signalling, is soluble haemojuvelin (HJV)[43].  Heparin and heparin-derivatives inhibit hepcidin excretion by interfering with BMP signalling.

Anaemia of inflammation and Castleman disease was improved in arthritic monkeys with anti-IL-6-receptor antibodies which suppress IL-6-induced hepcidin production.[44],[45]  Effective hepcidin suppressors like prolyl-/aspargine  hydroxylases can inhibit key initiators of the cellular hypoxic response and restore natural iron regulation in anaemia.[46],[47]    Efficacy of hepcidin-related therapies needs further investigation to address safety and long-term efficacy and to clarify risks and benefits, e.g. by large, well-designed clinical studies.

 CONCLUSION

Disruptions in iron homeostasis from iron deficiency and iron overload are common human diseases.  The hormone hepcidin plays a major role in the control of body iron homeostasis.  Hepcidin modulating agents have interesting therapy potentials for treating iron-related disorders.

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