Hepcidin, a small peptide synthesized in the liver, controls extracellular iron by regulating its intestinal absorption, placental transport, recycling by macrophages, and release from stores.
CHEMICAL STRUCTURE AND IMAGES
When relevant for the function
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- Secondary structure
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Protein Aminoacids Percentage
SYNTHESIS AND TURNOVER
Hepcidin inhibits the cellular efflux of iron by binding to and inducing the degradation of ferroportin (FPN), the sole iron exporter in iron-transporting cells, thereby blocking iron flow into plasma.
Considering the tissue distribution of ferroportin, the hepcidin-ferroportin interaction explains the efferent arm of iron homeostasis because it can control the iron absorption in the duodenum, as well as the release of iron from macrophages and hepatocytes.
Hepcidin synthesis is regulated by:
Fig 1 A model of homeostatic regulation of plasma iron. When iron levels are high, molecules such as the hemochromatosis gene product (HFE), hemojuvelin (HJV) and transferrin receptor 2 (TfR2) increase hepatic hepcidin expression. HJV is proposed to act as a co-receptor for bone morphogenic protein (BMP) ligands and BMP receptors (BMP-R). Upon binding to HJV, the ligand and two BMPRs on the cell surface, the intracellular BMP signaling pathway is activated. This in turn activates the SMAD signaling pathway to induce hepcidin expression. However, the pathway by which HFE and TfR2 induce hepcidin expression is unclear. It is suggested that HJV and soluble HJV (sHJV) modulates hepcidin expression through activating bone morphogenetic protein (BMP) signaling. Infection and inflammation can result in cytokines, such as interleukin-6 (IL-6) stimulating hepcidin expression through molecular pathways that could include binding of STAT3 to the hepcidin promoter. Hepcidin then binds to ferroportin-1 (FPN1) on the surface of macrophages, enterocytes and hepatocytes. The complex is then internalized and degraded, decreasing iron release from macrophages and hepatocytes and reducing intestinal iron uptake. It is suggested that hepcidin also decreases expression of proteins involved in intestinal iron absorption, such as duodenal cytochrome-b (Dcytb) and divalent metal transporter-1 (DMT1), although the mechanism and extent of control is unknown. By contrast, increased erythropoietic activity suppresses hepcidin expression, as do anemia and hypoxia. How these three processes inhibit hepcidin expression is unclear, but they are closely related. Solid lines indicate a demonstrated pathway; dashed lines indicate an unknown mechanism. For simplicity, the sensing of iron, oxygen, and microbes is shown taking place in a hepatocyte. It is likely that other cell types sense these stimuli and generate second messengers that converge on the hepatocyte. For inflammation, IL-6 serves as a second messenger of microbial infection or equivalent inflammatory stimuli.
Regulation by Iron
Hepcidin induction by iron is homeostatic because increased plasma hepcidin would act to inhibit further intestinal iron absorption and iron release from stores. However, the mechanism of hepcidin regulation by iron is turning out to be unexpectedly complex.
Although hepatocytes are the main sources of hepcidin, and the simplest model would place the iron sensor there (Fig 1), it is not certain that iron sensing takes place in hepatocytes.
The hepcidin mRNA lacks any stem-loop structures containing the consensus IRE motif for binding of iron-regulatory proteins. Perhaps the best clue about hepcidin regulation by iron comes from the studies of genes involved in hereditary hemochromatosis. [E Nameth et al, 2006]
Regulation by Oxygen and Anemia
Hepcidin production is suppressed by anemia and hypoxemia.
Most of the iron absorbed from the diet or recycled from hemoglobin is destined for developing erythrocytes. The production of erythrocytes is physiologically increased in response to blood loss or hypoxia.
When oxygen delivery is inadequate, the homeostatic response is to produce more erythrocytes. Thus hepcidin levels decrease, its inhibitory effects diminish, and more iron is made available from the diet and from the storage pool in macrophages and hepatocytes. Although the human hepcidin promoter contains several consensus binding sites for hypoxia-inducible factor, these are not typical and not conserved
in other mammals, and the molecular pathways that regulate hepcidin in response to hypoxia are not known [T Ganz et al, 2006].
Regulation by Inflammation
Hepcidin is not only an iron-regulatory hormone but also importantly links iron metabolism to host defense and inflammation. Hepcidin synthesis is markedly induced by infection and inflammation.
These effects are mediated by inflammatory cytokines, predominantly IL-6.
The cytokine IL-6 is the key inducer of hepcidin synthesis during inflammation [T Ganz et al, 2006, E Nameth et al, 2006].
Fig 2 Role of hepcidin in iron regulation. Hepcidin regulates intestinal iron absorption, iron recycling by macrophages, and iron release from hepatic stores. In turn, hepcidin secretion is regulated by iron stores, oxygenation, and inflammatory signals, chiefly IL-6. RBC, red blood cells.
Dysregulation of hepcidin or its receptor ferroportin results in a spectrum of iron disorders:
- anemia of inflammation
- hereditary hemochromatosis
- In inflammatory disorders and infections, cytokine induced hepcidin excess contributes to development of anemia of inflammation , characterized by hypoferremia and anemia despite adequate iron stores.
- Inappropriately low hepcidin production due to mutations in the hepcidin gene or its putative regulators appears to be the cause of most types of hereditary hemochromatosis, the iron overload disease characterized by excessive dietary iron uptake and iron deposition in vital organs. The remaining types of hereditary iron overload disorders are caused by mutations in ferroportin that either render the protein nonfunctional (not exporting iron, resulting in “ferroportin disease”) or unresponsive to hepcidin (excessively exporting iron, resulting in more typical hemochromatosis).
Fig 3 Anemia of inflammation and hemochromatosis represent opposite ends of the phenotypic spectrum of iron-related disorders. Anemia of inflammation (AI) is characterized by high levels of hepcidin, which leads to iron deficiency and iron-rich macrophages. In contrast, in hemochromatosis , hepcidin levels are low with enhanced intestinal absorption and whole-body iron overload. Macrophages in hemochromatosis are iron-depleted. Juvenile hemochromatosis (JH) and adult-onset hereditary hemochromatosis (HH) both show iron overload with iron-depleted macrophages, but the phenotype is more severe in juvenile hemochromatosis.
Papers Verga Falzacappa MV