Albertine Donker

Chapter 2 56 Although the machinery of systemic and cellular iron homeostasis is separated, crosstalk exists between distinct control systems, 11,14,15 on the level of ferroportin, HIF2α and TfR1. 14,16 First, ferroportin, that as iron exporter is a critical factor for plasma iron supply, is subject to both systems. Iron status is sensed on the systemic level and communicated post-translationally via hepcidin, thereby influencing the activity of ferroportin. On the cellular level, iron levels post-transcriptionally regulate ferroportin mRNA via the IRE/IRP system. 20 Second, HIF2α is involved in EPO-mediated regulation of hepcidin levels, but HIF2α mRNA is also a target of the IRE/IRP system. Third, systemic Tf-Fe 2 displaces TfR1 from HFE inside the hepatocyte, which then subsequently forms a complex with TfR2 and HJV to promote BMP/SMAD signaling leading to HAMP and subsequent hepcidin production. On the cellular level, TfR1 expression is modulated by the IRE/IRP system. 14,21 More interconnections between the systemic and cellular iron homeostasis might exist and although the cornerstones of the two systems have been identified, future research is needed to further unravel how the two systems tango and collaborate. Systemic iron homeostasis and the central role of hepcidin In physiological circumstances, intestinal iron absorption is enhanced in situations of increased iron demands (for example during periods of rapid growth in infancy, childhood and pregnancy and during periods of blood loss e.g. menses). 11 On the other hand, iron absorption is depressed in case of (imminent) IO Importantly, the human body cannot excrete iron in a regulated way. Therefore, effective communication and fine-tuning between enterocytes, erythroid precursors, hepatocytes and macrophages is crucial in order to optimally distribute iron between the different body compartments and to prevent both ID and IO. Hepcidin, a 25-amino acid peptide hormone that is predominantly synthesized by hepatocytes and excreted by the kidneys, has emerged as the key regulator of systemic iron homeostasis. 7 Hepcidin acts by binding to ferroportin, thereby inducing its degradation and internalization and subsequently blocking iron export out of the enterocytes, hepatocytes, and macrophages into the plasma. Because of this characteristic hepcidin is able to orchestrate iron flows in the body and to regulate iron uptake and iron utilization in favor of storage or vice versa. 11,14 The synthesis of hepcidin is controlled by certain physiologic and pathologic triggers that reflect circulating and stored iron levels, erythropoietic activity, hypoxia (see above) and inflammatory signals. 7,11,14,22-24