Iron Regulation and Hepcidin

Iron is an important metal in the body necessary for heme and iron-sulfur production, hemoglobin synthesis, and oxidation of cellular reactions. Regulation of iron is crucial for normal homeostasis. Although iron is essential for life, excess iron is toxic. Excess iron promotes Fenton chemistry to produce hydroxyl radicals and other reactive oxygen species (ROS), which damage important structures such as DNA and lipids (Wessling-Resnick, 2017). Since oxygen metabolism and iron are closely intertwined, tissues and organs that have high oxidative metabolism are very susceptible to ROS damage and consequences of an overload of iron (Wessling-Resnick, 2017). The mechanism of intestinal iron regulation is outlined in Figure 1.

Figure 1. Adapted from Camaschella et. al., 2020. Intestinal iron absorption overview: DMT1 takes up Fe(II), which is reduced by Dcytb. HEPH oxidizes Fe(II) to Fe(III). Unused Fe stored in ferritin or exported to TF by FPN. Abbreviations: DMT1, divalent metal transporter 1; Dcytb, duodenal cytochrome B reductase; HEPH, hephaestin; TF, transferrin; FPN, ferroportin.

On the luminal side of the enterocyte, the metal transporter DMT1 takes up ferrous iron, which is reduced by Dcytb (Camaschella et. al., 2020). After hephaestin (HEPH) oxidizes ferrous iron to ferric iron, iron that is not used by the cell is either stored in ferritin or exported to circulating transferrin (TF) by ferroportin (FPN) (Camaschella et. al., 2020). The expression of the apical and basolateral transporters, DMT1 and FPN, is stimulated by hypoxia inducible factor (HIF)-2α (Camaschella et. al., 2020).

The liver is the known central regulator of iron homeostasis. Hepatocytes have been known to be storage reservoirs for iron, absorbing dietary iron from the portal circulation, and releasing iron into the hepatic circulation (Camaschella et. al., 2020). Its deregulation leads to various iron disorders, including hereditary hemochromatosis. The identification of the hepcidin protein led to a more detailed understanding of the role of the liver in iron regulation. Generally, hepcidin controls iron transport to the plasma by inducing lysosomal degradation of the iron transporter ferroportin in enterocytes, macrophages, and hepatocytes (Nemeth et. al., 2004). The expression of hepcidin is detailed in Figure 2.

Figure 2. Adapted from Camaschella et. al 2020. Schematic of hepcidin regulation by BMP-SMAD pathway: LSEC produce BMP2, which binds to the BMP receptor type II and phosphorylates the BMP receptors type I (ALK3) to activate SMAD 1/5/8. SMAD1/5/8 associates with SMAD4 to lead to the expression of hepcidin. Abbreviations: LSEC, liver endothelial cells; TFR1, transferrin receptor 1; HFE, HFE protein.

Liver endothelial cells (LSEC) produce BMP2, which binds to BMP receptor type II, phosphorylating the BMP receptors type I (ALK3) to activate SMAD1/5/8 (Camaschella et. al., 2020). SMAD1/5/8 associates with SMAD4 and translocates to the nucleus, binding BMP responsive elements (BRE) in the hepcidin promoter (Camaschella et. al., 2020).

In iron overload, HFE is displaced from transferrin receptor 1 (TFR1) in the presence of increased diferric transferrin, which enables iron uptake and stabilizes HFE interaction with TFR2. The new HFE-TFR2 interaction allows ALK3 to be signaled. Hemojuvelin (HJV) acts as a BMP co-receptor (Camaschella et. al., 2020). Iron increases the production of BMP6 by LSEC, which activates ALK2 and most likely ALK3 (denoted by dotted arrow) (Camaschella et. al., 2020). Even though ALK3 is activated, it does not reach the surface of the cell in order to aid in hepcidin expression. This hinderance causes low levels of hepcidin, leading to an increase in iron absorption.

HFE Protein

The HFE protein controls the normal regulation of hepatic synthesis of hepcidin. HFE is a protein comprised of 343 amino acids made up of a signal peptide, an extracellular transferrin receptor-binding region (α1 and α2), an immunoglobulin-like domain (α3), a transmembrane region, and a short cytoplasmic tail as seen in Figure 3 (Barton et. al., 2015). HFE binds β2M to form a heterodimer expressed at the cell surface and interacts with other proteins on the cell surface to detect the amount of iron in the body (Barton et. al., 2015).

Figure 3. Adapted from Barton et. al., 2015. HFE protein associated with β2-microglobulin (β2M) at the cell surface. Abbreviatons: cyto, cytoplasmic tail; tm, transmembrane domain.

Normally, TFR1 binds to TF, which causes iron to enter liver cells. When HFE is bound to TFR1, the receptor cannot bind to TF. However, at high levels of iron, HFE is displaced from TFR1 onto TFR2. This displacement causes TFR1 to bind TF and allow iron entry, and HFE binds to TFR2 and leads to the expression of low levels of hepcidin, leading to iron uptake. Proper functioning of the HFE protein results in iron sensing and absorption at normal regulated levels.

All normal cells and tissues express small amounts of HFE (Barton et. al., 2015). The concentration of HFE in human enterocytes decreases from villous crypts to villous tips and from duodenum to ileum (Waheed et. al., 1999).

TFR1 and TFR2

Transferrin is required for iron delivery into cells through TFR1. TFR1 will only bind TF with iron attached, either monoferric or diferric.

Figure 4. Adapted from Aisen, 2004. Schematic of iron metabolism step of TF-to-cell. Abbreviations: AP-2, adaptor protein complex; DMT1, divalent metal transporter; HFE, HFE protein.

As seen in Figure 4, when the TF binds to the TFR1, the assembly is internalized by an adaptor protein complex (AP-2). This internalization leads to rapid maturation and internalization to a proton-pumping, pH-lowering endosome (Aisen, 2004). Iron is freed from the TF by the divalent metal transporter (DMT1) (Fleming et. al., 2005). The iron-less TF returns to the cell surface to be used in another cycle of iron transport (Aisen, 2004). This iron-binding process onto the TF regulates the function of TFR1.

This process is how TF and TFR1 function normally, but this is the same process that occurs in hemochromatosis because HFE disassociates from TFR1 because it starts to bind to the excess TF that is present. The normal function of TF and TFR1 is still occurring in the disease, but the completion of the process is aiding in the actions of the mutations. The binding of TF and TFR1, in place of the HFE-TFR1 complex, leads to a more stable association of HFE and TFR2.

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Molecular Detail

Effects, Detection, and Treatments

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References

Aisen, P. Transferrin Receptor 1. The International Journal of Biochemistry & Cell Biology 200436 (11), 2137–2143. 

Barton, J. C.; Edwards, C. Q.; Acton, R. T. HFE Gene: Structure, Function, Mutations, and Associated Iron Abnormalities. Gene 2015574 (2), 179–192. 

Camaschella, C.; Nai, A.; Silvestri, L. Iron Metabolism and Iron Disorders Revisited in the Hepcidin Era. Haematologica 2020

Fleming, R. E.; Britton, R. S.; Waheed, A.; Sly, W. S.; Bacon, B. R. Pathophysiology of Hereditary Hemochromatosis. Semin Liver Dis 200525 (4), 411–419. 

Nemeth, E.; Tuttle, M. S.; Powelson, J.; Vaughn, M. B.; Donovan, A.; Ward, D. M.; Ganz, T.; Kaplan, J. Hepcidin Regulates Cellular Iron Efflux by Binding to Ferroportin and Inducing Its Internalization. Science 2004306 (5704), 2090–2093.

Waheed, A.; Parkkila, S.; Saarnio, J.; Fleming, R. E.; Zhou, X. Y.; Tomatsu, S.; Britton, R. S.; Bacon, B. R.; Sly, W. S. Association of HFE Protein with Transferrin Receptor in Crypt Enterocytes of Human Duodenum. Proc Natl Acad Sci U S A 199996 (4), 1579–1584. 

Wessling-Resnick, M. Excess Iron: Considerations Related to Development and Early Growth. Am. J. Clin. Nutr. 2017106 (Suppl 6), 1600S-1605S. 

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