Hepcidin and Iron in Health and Disease

Abstract

Hepcidin, the iron-regulatory hormone, determines plasma iron concentrations and total body iron content. Hepcidin, secreted by hepatocytes, functions by controlling the activity of the cellular iron exporter ferroportin, which delivers iron to plasma from intestinal iron absorption and from iron stores. Hepcidin concentration in plasma is increased by iron loading and inflammation and is suppressed by erythropoietic stimulation and during pregnancy. Hepcidin deficiency causes iron overload in hemochromatosis and anemias with ineffective erythropoiesis. Hepcidin excess causes iron-restrictive anemias including anemia of inflammation. The development of hepcidin diagnostics and therapeutic agonists and antagonists should improve the treatment of iron disorders.

Keywords: anemia; hepcidin; inflammation; iron; iron overload.

Figure 1

Hepcidin has a homeostatic role in conditions associated with physiological hepcidin stimulation (a) or suppression (b) and a pathological role in iron-restrictive disorders (c) and iron-overload disorders (d). Iron flows are shown in shades of blue indicative of intensity. Hepcidin and its effects are shown in red; normal and pathological hepcidin modulators are shown in gold. Abbreviations: Fe-Tf, iron-transferrin; MT-2, matriptase-2; RBC, red blood cell. Figure adapted from Reference with permission.

Figure 2

Molecular mechanisms of hepcidin regulation. Center: Iron regulates hepcidin through two distinct mechanisms. Extracellular iron in the form of holotransferrin (Fe-Tf) is sensed by the two transferrin receptors (TFR1 and TFR2). Binding of Fe-Tf to its receptors promotes hemochromatosis protein (HFE) interaction with TFR2 instead of TFR1, and the HFE/TFR2 complex then sensitizes the bone morphogenetic protein (BMP) receptor to its ligands BMP2 and −6 or the BMP2/6 heterodimer. HFE may also directly stabilize the BMP receptor by preventing its ubiquitination. Hemojuvelin (HJV), a membrane-linked BMP coreceptor, potentiates the BMP receptor activation. Once activated, BMP receptors initiate SMAD signaling, which increases hepcidin transcription. Increased intracellular iron in the liver enhances BMP6 and −2 production by liver sinusoidal endothelial cells, eventually leading to activation of the BMP receptor on hepatocytes. Under low-iron conditions, low Fe-Tf concentrations and low intracellular iron both lead to decreased BMP pathway signaling and decreased hepcidin mRNA expression. Furthermore, matriptase-2 (MT-2) protease is stabilized in low-iron conditions and inhibits and cleaves HJV and other molecules of the BMP pathway, thus further decreasing the SMAD signaling. Left: Inflammation stimulates hepcidin production by increasing the transcription of hepcidin through the interleukin (IL)-6–JAK-STAT pathway. Right: Erythropoiesis activation leads to increased production of erythroferrone (ERFE) by erythroblasts. ERFE then inhibits BMP signaling by binding to BMP2/6 and interfering with its interaction with the BMP receptor, thereby lowering hepcidin and making more iron available for erythropoiesis.