Out of balance--systemic iron homeostasis in iron-related disorders

Abstract

Iron is an essential element in our daily diet. Most iron is required for the de novo synthesis of red blood cells, where it plays a critical role in oxygen binding to hemoglobin. Thus, iron deficiency causes anemia, a major public health burden worldwide. On the other extreme, iron accumulation in critical organs such as liver, heart, and pancreas causes organ dysfunction due to the generation of oxidative stress. Therefore, systemic iron levels must be tightly balanced. Here we focus on the regulatory role of the hepcidin/ferroportin circuitry as the major regulator of systemic iron homeostasis. We discuss how regulatory cues (e.g., iron, inflammation, or hypoxia) affect the hepcidin response and how impairment of the hepcidin/ferroportin regulatory system causes disorders of iron metabolism.

Figure 1

Iron absorption in the intestine. In the human diet, iron is present as heme or nonheme iron. Absorption of heme iron (Fe²⁺) is incompletely understood and likely mediated by a heme transporter. Intracellularly, iron is released from heme by hemoxygenase-1 (HO-1). Nonheme iron (Fe³⁺) is reduced by the membrane-associated ferric reductase CYBRD1 (DCYTB) for transport into the intestinal enterocyte by the divalent metal transporter (DMT1). Within the enterocyte iron can be stored in ferritin or exported into the blood stream by the iron exporter ferroportin (FPN1, SLC40A1). FPN expression is controlled by hepcidin. Hephaestin, a multicopper oxidase is required to incorporate two Fe³⁺ into one transferrin molecule (Tf). Hypoxia inducible factor 2 (HIF-2) controls CYBRD1, DMT1, FPN, and HO-1 mRNA expression (depicted in green) and iron regulatory proteins (IRPs) post-transcriptionally control the expression of DMT1, ferritin, and FPN (depicted in orange).

Figure 2

Regulation of hepatic hepcidin production. Hepatic hepcidin synthesis is regulated by iron, bone morphogenetic protein signaling, inflammation, erythropoiesis, hypoxia, or endocrine stimuli. FPN1, which is expressed predominantly in hepatocytes, macrophages and enterocytes is internalized and degraded following hepcidin binding. Iron is transported in the blood bound to transferrin. Most iron is required for erythropoiesis. Aging erythrocytes that exceed a life-span of approximately 120 days are recycled in macrophages. Transferrin-iron is a critical indicator for systemic iron homeostasis and regulator of hepcidin expression.

Figure 3

Regulation of hepatic hepcidin induction at the cellular level. Transferrin bound iron (Tf-Fe) is monitored by an “iron sensing complex”, which consists of the transferrin receptors (TfR) 1 and 2, HFE, and HJV. HJV is a glykosylphosphatidylinositol (GPI)-linked membrane associated protein that functions as a BMP coreceptor, and enhances bone morphogenetic protein (BMP) signaling. Binding of one of the more than 25 known BMP ligands (such as BMP6) to type I and II BMP receptors induces the type II receptor to phosphorylate and activate the BMP type I receptor. There are four BMP type I receptors (called ALK1, ALK2, ALK3, and ALK6), and three BMP type II receptors (BMPR2, ActRIIA, and ActRIIB). The activated BMP type I receptor leads to phosphorylation of intracellular signaling molecules called receptor associated SMAD proteins (R-SMADs). Phosphorylated R-SMADs transfer together with SMAD 4 to the hepatocyte nucleus and induce hepcidin transcription. SMAD6 and SMAD7 are inhibitory SMADs. BMPER, the BMP endothelial cell precursor-derived regulator inhibits BMP signaling and decreases hepatic hepcidin expression. MicroRNA 122 is activated by HFE or HJV and inhibits the latter in a negative feedback regulatory loop. The transmembrane serine protease (TMPRSS6) cleaves HJV and thereby decreases BMP-mediated hepcidin induction. Neogenin, a transmembrane protein known to interact with HJV, can also interact with TMPRSS6 to enable HJV cleavage in transfected cells. Soluble HJV is generated by proprotein convertase activity and has been proposed to sequester BMPs. Inflammatory stimuli such as interleukin-6 (IL-6) induce hepcidin transcription via the JAK/STAT signaling pathway. A SMAD- and a STAT-binding element have been identified in the hepcidin promoter.

Figure 4

Alterations of systemic iron homeostasis caused by imbalances of the Hepcidin/Ferroportin regulatory system.

Figure 5

Prevalence of anemia in the general population worldwide.