Hypoxia-Inducible Factors Link Iron Homeostasis and Erythropoiesis

Iron is required for efficient oxygen transport, and hypoxia signaling links erythropoiesis with iron homeostasis. Hypoxia induces a highly conserved signaling pathway in cells under conditions of low levels of O2. One component of this pathway, hypoxia-inducible factor (HIF), is a transcription factor that is highly active in hypoxic cells. The first HIF target gene characterized was EPO, which encodes erythropoietin—a glycoprotein hormone that controls erythropoiesis. In the past decade, there have been fundamental advances in our understanding of how hypoxia regulates iron levels to support erythropoiesis and maintain systemic iron homeostasis. We review the cell type–specific effects of hypoxia and HIFs in adaptive response to changes in oxygen and iron availability as well as potential uses of HIF modulators for patients with iron-related disorders. Iron is required for efficient oxygen transport, and hypoxia signaling links erythropoiesis with iron homeostasis. Hypoxia induces a highly conserved signaling pathway in cells under conditions of low levels of O2. One component of this pathway, hypoxia-inducible factor (HIF), is a transcription factor that is highly active in hypoxic cells. The first HIF target gene characterized was EPO, which encodes erythropoietin—a glycoprotein hormone that controls erythropoiesis. In the past decade, there have been fundamental advances in our understanding of how hypoxia regulates iron levels to support erythropoiesis and maintain systemic iron homeostasis. We review the cell type–specific effects of hypoxia and HIFs in adaptive response to changes in oxygen and iron availability as well as potential uses of HIF modulators for patients with iron-related disorders. Iron, an essential nutrient, is required for oxygen delivery and is a cofactor in several enzymatic and redox reactions. In mammals, 70% of iron is found in red blood cells (RBCs) and 6% is a component of iron-containing proteins, which are required for respiration, energy metabolism, and endobiotic and xenobiotic metabolism. The remaining 24% is stored in ferritin. Iron levels are controlled by a multi-tissue homeostatic process in which dietary iron is absorbed through the proximal small intestine. Dietary iron (Fe3+) is reduced by apical ferric reductase duodenal cytochrome b (DCYTB) to ferrous iron (Fe2+) and imported into the enterocyte via the apical iron transporter, divalent metal transporter 1 (DMT1, also known as NRAMP2 or DCT1 and encoded by SLC11A2).1Fleming M.D. Trenor III, C.C. Su M.A. et al.Microcytic anaemia mice have a mutation in Nramp2, a candidate iron transporter gene.Nat Genet. 1997; 16: 383-386Crossref PubMed Google Scholar, 2Gunshin H. Mackenzie B. 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Specific stimuli can have different effects on HIF signaling. Low levels of iron, reductions in levels of O2, or increases in mitochondrial reactive oxygen species lead to activation of different subsets of HIF target genes. For example, low levels of iron in the intestine lead to activation of HIF-2α and its target genes, including DMT1 and CYBRD1 (which encodes DCYTB), but do not alter expression of vascular endothelial growth factor (VEGF), which is frequently induced under conditions of hypoxia.35Shah Y.M. Matsubara T. Ito S. et al.Intestinal hypoxia-inducible transcription factors are essential for iron aborption following iron deficiency.Cell Metab. 2009; 9: 152-164Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar The mechanisms of these differential gene expression patterns are not clear and might involve specific or relative inhibition of PHDs. 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HIF-2α is therefore critical in maintaining a functional microenvironment during hematopoiesis, rather than a bone marrow cell factor, required for proliferation and differentiation of HSCs.55Scortegagna M. Morris M.A. Oktay Y. et al.The HIF family member EPAS1/HIF-2alpha is required for normal hematopoiesis in mice.Blood. 2003; 102: 1634-1640Crossref PubMed Scopus (151) Google Scholar Hepcidin (encoded by HAMP) is a peptide hormone that is the master regulator of iron levels in humans and other mammals. It was initially discovered as an antimicrobial peptide that was mainly synthesized in the liver, could be detected in the urine, and was induced by inflammation.62Krause A. Neitz S. Magert H.J. et al.LEAP-1, a novel highly disulfide-bonded human peptide, exhibits antimicrobial activity.FEBS Lett. 2000; 480: 147-150Crossref PubMed Scopus (1031) Google Scholar, 63Park C.H. Valore E.V. 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