Iron regulation by hepcidin
Ningning Zhao, … , An-Sheng Zhang, Caroline A. Enns
Ningning Zhao, … , An-Sheng Zhang, Caroline A. Enns
Published June 3, 2013
Citation Information: J Clin Invest. 2013;123(6):2337-2343. https://doi.org/10.1172/JCI67225.
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Iron regulation by hepcidin

Abstract

Hepcidin is a key hormone that is involved in the control of iron homeostasis in the body. Physiologically, hepcidin is controlled by iron stores, inflammation, hypoxia, and erythropoiesis. The regulation of hepcidin expression by iron is a complex process that requires the coordination of multiple proteins, including hemojuvelin, bone morphogenetic protein 6 (BMP6), hereditary hemochromatosis protein, transferrin receptor 2, matriptase-2, neogenin, BMP receptors, and transferrin. Misregulation of hepcidin is found in many disease states, such as the anemia of chronic disease, iron refractory iron deficiency anemia, cancer, hereditary hemochromatosis, and ineffective erythropoiesis, such as β-thalassemia. Thus, the regulation of hepcidin is the subject of interest for the amelioration of the detrimental effects of either iron deficiency or overload.

Authors

Ningning Zhao, An-Sheng Zhang, Caroline A. Enns

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Figure 1

Models for control of hepcidin expression by iron.

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Models for control of hepcidin expression by iron. Efficient hepcidin ex...
Efficient hepcidin expression in hepatocytes requires an intact BMP signaling pathway, HJV, neogenin, TfR2, HFE, and BMP6. (A) Under high iron conditions, increased loading of Tf with iron stabilizes TfR2, disrupts the HFE-TfR1 interaction, and induces BMP6 secretion from the nonparenchymal cells of the liver, which facilitates the formation of a complex consisting of the BMP receptor/BMP6/HJV/neogenin/TfR2/HFE to induce hepcidin expression. (B) Low iron conditions increase MT2, which induces the cleavage of hepatic HJV. Decreased Tf saturation in the circulation destabilizes TfR2 protein and facilitates the HFE-TfR1 interaction. Low iron levels in the liver reduce BMP6 secretion from the nonparenchymal cells, consequently blunting BMP signaling and lowering hepcidin expression. (C) Inflammation induces the expression of IL-6 and activin B in the liver, which activates the transcription of hepcidin via the STAT3/JAK2 pathway and the BMP signaling pathway, respectively.