Fig. 1.

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Fig. 1. The iron cycle and adaption to iron deficiency: adapted from reference [3,8,9,16]. (A) Iron trafficking: the daily iron requirement is 20-25 mg; most iron is recycled from senescent erythrocytes stored in reticuloendothelial macrophage. In addition, 1-2 mg of dietary iron is absorbed by duodenal enterocyte via divalent metal transporter 1 (DMT1) on the apical brush-border membrane after reduction of Fe3+ to Fe2+ through duodenal cytochrome B (DcytB). Although not well known for heme iron, when it enters the intestinal cell by endocytosis, it is released into the cell while being oxidized by heme oxygenase 1 (HOX1). Each cell exports iron through ferroportin (FPN) with the help of hephaestin (HFE) or ceruloplasmin, which convert newly transported Fe2+ to Fe3+. In the plasma, transferrin captures iron and transports it to the organs, which store or utilize iron. Excess iron is also stored in the liver and macro-phages as a reserve. (B) Iron homeostasis: in the hepatocytes, bone morphogenic protein (BMP)-SMAD signaling cascade, the main activator of hepcidin, increases hepcidin transcription. BMP6 is produced by liver sinusoidal endothelial cells (LSEC) and neogenin (NEO1) regulates the expression of hepcidin by stabilization of hemojuvelin (HJV), a co-receptor of BMP. In addition, STAT3 signaling induced by the inflammatory cytokine IL6 also increases hepcidin transcription. The HFE, displaced from the transferrin receptor (TfR)- 1, stabilizes the surface TfR2 to enhance ALK3 signal and increase hepcidin transcription. Subsequently, high concentration of hepcidin binds and degrades FPN in the enterocyte, macrophage, and hepatocyte, blocking iron export. (C) Adaptation to iron deficiency: low levels of BMP6 are produced by LSEC, and HJV is cleaved from the hepatocyte surface by the transmembrane serine protease 6 (TMPRSS6). In addition, iron deficiency induced hypoxia-inducible factor 2α (HIF-2α) increases the expression of the DMT1 to increase the transfer of dietary iron, and the production of erythropoietin (EPO) to stimulate erythropoiesis. Increased erythroferrone (ERFE) blocks the hepcidin pathway; however, the molecular mechanism of hepcidin inhibition by ERFE remains unknown. Also, TfR2 is not stabilized on the cell surface in the absence of the ligand diferric transferrin. As a result, low hepcidin levels increase iron absorption by enterocytes and recycling by macrophages through increased activity of the iron exporter FPN.
Clin Pediatr Hematol Oncol 2020;27:101-12
© 2020 Clin Pediatr Hematol Oncol