Iron metabolism and iron disorders revisited in the hepcidin era

Abstract

Iron is biologically essential, but also potentially toxic; as such it is tightly controlled at cell and systemic levels to prevent both deficiency and overload. Iron regulatory proteins post-transcriptionally control genes encoding proteins that modulate iron uptake, recycling and storage and are themselves regulated by iron. The master regulator of systemic iron homeostasis is the liver peptide hepcidin, which controls serum iron through degradation of ferroportin in iron-absorptive enterocytes and iron-recycling macrophages. This review emphasizes the most recent findings in iron biology, deregulation of the hepcidin-ferroportin axis in iron disorders and how research results have an impact on clinical disorders. Insufficient hepcidin production is central to iron overload while hepcidin excess leads to iron restriction. Mutations of hemochro-matosis genes result in iron excess by downregulating the liver BMP-SMAD signaling pathway or by causing hepcidin-resistance. In iron-loading anemias, such as β-thalassemia, enhanced albeit ineffective ery-thropoiesis releases erythroferrone, which sequesters BMP receptor ligands, thereby inhibiting hepcidin. In iron-refractory, iron-deficiency ane-mia mutations of the hepcidin inhibitor TMPRSS6 upregulate the BMP-SMAD pathway. Interleukin-6 in acute and chronic inflammation increases hepcidin levels, causing iron-restricted erythropoiesis and ane-mia of inflammation in the presence of iron-replete macrophages. Our improved understanding of iron homeostasis and its regulation is having an impact on the established schedules of oral iron treatment and the choice of oral versus intravenous iron in the management of iron deficiency. Moreover it is leading to the development of targeted therapies for iron overload and inflammation, mainly centered on the manipulation of the hepcidin-ferroportin axis.

Figure 1.

The iron cycle. Iron (Fe) circulates bound to transferrin to be released to all organs/tissues through transferrin receptor 1. Most iron (20-25 mg) recycled by macrophages, which phagocytize senescent red blood cells (RBC), is supplied to the bone marrow for RBC production. The daily uptake of dietary iron by duodenal enterocytes is 1-2 mg; the same amount is lost through cell desquamation and blood loss. Excess iron is stored in the liver and macrophages as a reserve. Arrows indicate directions. Numbers (in mg) are a mean estimate. (A) Focus on intestinal iron absorption. The metal transporter DMT1 takes up ferrous iron, reduced by DCYTB, on the luminal side of the enterocyte. Iron not used inside the cell is either stored in ferritin (FT) or exported to circulating transferrin (TF) by ferroportin (FPN), after ferrous iron is oxidized to ferric iron by hephaestin (HEPH). Hypoxia inducible factor (HIF)-2α, stabilized by local hypoxia, stimulates the expression of the apical (DMT1) and basolateral (FPN) transporters. Heme, after entering the cell through an unknown mechanism, is converted to iron by heme oxygenase. (B) Focus on the iron recycling process. Macrophages recover iron from phagocytized RBC after heme is degraded by heme oxygenase. They also recover heme from hemoglobin (Hb)-haptoglobin (HP) or heme-hemopexin (HPX) complexes. Iron not used inside the cells is either stored in FT or exported to the circulation by FPN with the cooperation of ceruloplasmin (CP). The latter is the preferential route in normal conditions.

Figure 2.

The regulation of hepcidin expression (adapted from Silvestri et al.). Schematic representation of a model of hepcidin regulation by two branches of the bone morphogenetic protein (BMP)-SMAD pathway, based on BMP knockout models,^,, in (A) iron overload, (B) iron deficiency, (C) erythropoiesis expansion and (D) inflammation. According to a recent study BMP2 and BMP6 work collaboratively in vivo, possibly as a heterodimer. (A) BMP2 produced by liver endothelial cells (LSEC) binds BMP receptor type II, which phosphorylates the BMP receptors type I (ALK3) to activate SMAD1/5/8. The latter associated with SMAD4 translocate to the nucleus to bind BMP responsive elements (BRE) in the hepcidin promoter. In iron overload increased diferric transferrin displaces HFE from transferrin receptor (TFR) 1 to enable iron uptake and stabilizes surface TFR2 potentiating ALK3 signaling. Hemojuvelin (HJV) acts as a BMP co-receptor, while the function of the other hemochromatosis HFE and TFR2 proteins in the pathway activation is still unclear. Iron increases the production of BMP6 by LSEC, thereby activating ALK2 and likely also ALK3 (indicated by a dotted arrow) in the pathway. (B) In iron deficiency TMPRSS6, stabilized on the cell surface, cleaves HJV and inactivates the BMP2-ALK3 branch of the pathway. TFR2 is destabilized by the lack of diferric transferrin and HFE binds TFR1. The BMP6 pathway is inactive in the absence of the ligand and also because ALK2 is inactivated by FKBP12 binding. Together with epigenetic regulation, this suppresses hepcidin expression. (C) Erythropoiesis enhanced by erythropoietin consumes a large amount of iron: low serum iron (and diferric transferrin) suppresses the BMP2-ALK3 pathway, while BMP6 and other BMP are sequestered by erythroferrone (ERFE) released by erythroid cells.^, The result is hepcidin inhibition. (D) Schematic representation of hepcidin regulation by inflammatory cytokines and of the pathogenesis of anemia of inflammation. Stimulated by inflammation [here indicated by lipopolysaccharide (LPS) through toll-like receptor 4 (TLR4)], macrophages produce interleukin-6 (IL6), which stimulates Janus kinase 2–signal transducer and activator of transcription 3 (JAK2-STAT3) signaling to upregulate hepcidin in association with the BMP-SMAD pathway.