Fig. 1

Systemic iron homeostasis. Trivalent iron is reduced by ferrireductases (DcytB) before its absorption through DMT1 in enterocytes. Once inside enterocytes iron binds with chaperones like PCBs. PCBs act like intracellular iron transporters that distribute this metal to ferritin depots and probably to FPN. FPN is the main exporter of iron out of cells. This action of FPN is helped by ferrioxidases (like Heph). After its export out of cells, iron is immediately bound to Tf. This complex circulates in plasma and finally binds with its target, which is TFR1. Systemic iron availability is controlled by hepcidin. Hepcidin is produced in hepatocytes in response to different stimuli. Iron-mediated pathways are the main factors that induce hepcidin expression. The most important pathways activate LSECs, which in turn produce BMP6. BMP6 acts in a paracrine manner through BMPR in hepatocytes. BMPR activates SMAD pathway, which induces hepcidin expression. Iron pathways induce hepcidin expression through membrane proteins, like TFR2 and HFE, as well. Inflammatory signals are also important upregulators of hepcidin by acting through JAK/STAT pathway. Negative control is realized through ERFE, which is produced from erythrocyte precursors. BMP6 bone morphogenetic protein 6, BMPR BMP receptor, DcytB duodenal cytochrome B, DMT1 divalent metal transporter 1, ERFE erythroferrone, FPN ferroportin, HAMP hepcidin antimicrobial peptide, Heph hephaestin, HFE hemochromatosis protein, JAK2/STAT3 janus kinase 2/signal transducer and activator of transcription 3, LSEC liver sinusoidal endothelial cells, PCB poly-(rC)-binding protein, SMAD S-mothers against decapentaplegic, TFR transferrin receptor