Iron homeostasis: An anthropocentric perspective

Abstract

The regulation of iron metabolism in biological systems centers on providing adequate iron for cellular function while limiting iron toxicity. Because mammals cannot excrete iron, mechanisms have evolved to control iron acquisition, storage, and distribution at both systemic and cellular levels. Hepcidin, the master regulator of iron homeostasis, controls iron flows into plasma through inhibition of the only known mammalian cellular iron exporter ferroportin. Hepcidin is feedback-regulated by iron status and strongly modulated by inflammation and erythropoietic demand. This review highlights recent advances that have changed our understanding of iron metabolism and its regulation.

Keywords: erythropoiesis; hepatocyte; infection; inflammation; iron metabolism.

Figure 1.

Iron flows and their regulation by the hepcidin–ferroportin axis. Iron homeostasis depends on the balance between iron losses and absorption, and the match between iron release from stores in recycling macrophages and hepatocytes versus its utilization for biological processes, primarily erythropoiesis. Small normal losses of iron are compensated for by the absorption of dietary iron in the duodenum. The hepcidin–ferroportin interaction regulates all the major flows of iron into plasma: the release of iron from duodenal enterocytes, recycling macrophages, and hepatocyte stores.

Figure 2.

Regulation of hepcidin production by paracrine BMP signaling. Homo- and heterodimeric BMP2 and BMP6 are secreted by hepatic sinusoidal endothelial cells and bind to tetrameric complexes of type 1 and 2 BMP receptors on hepatocytes. Activation of the BMP receptor complex by BMP binding transcriptionally stimulates hepcidin production by hepatocytes. BMP secretion by sinusoidal endothelial cells increases during high-iron conditions and stimulates hepcidin production by hepatocytes. Additional iron-regulatory mechanisms in hepatocytes utilize transferrin receptors as sensors and modulate the BMP receptor signal, depending on plasma iron–transferrin concentration.