Unit for the Study of Iron Metabolism, University of Modena and Reggio Emilia, Via del Pozzo 71, 41100 Modena, Italy
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ABSTRACT |
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Iron is essential for fundamental cell functions but is also a catalyst for chemical reactions involving free radical formation, potentially leading to oxidative stress and cell damage. Cellular iron levels are therefore carefully regulated to maintain an adequate substrate while also minimizing the pool of potentially toxic "free iron." The main control of body iron homeostasis in higher organisms is placed in the duodenum, where dietary iron is absorbed, whereas no controlled means of eliminating unwanted iron have evolved in mammals. Hereditary hemochromatosis, the prototype of deregulated iron homeostasis in humans, is due to inappropriately increased iron absorption and is commonly associated to a mutated HFE gene. The HFE protein is homologous to major histocompatibility complex class I proteins but is not an iron carrier, whereas biochemical and cell biological studies have shown that the transferrin receptor, the main protein devoted to cellular uptake of transferrin iron, interacts with HFE. This review focuses on recent advances in iron research and presents a model of HFE function in iron metabolism.
HFE; transferrin; transferrin receptor; divalent metal transport 1; ferroportin1/IREG1/MTP1
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ARTICLE |
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IRON IS A MAJOR COMPONENT of the Earth's crust, but its own chemistry greatly limits utilization and also sets the basis for its toxicity. Environmental iron exists in the ferric (Fe3+) form, which is almost insoluble in water at neutral pH. In addition, iron, as a polar hydrophilic metal ion, is unable to cross membranes. Therefore, specialized transport systems and membrane carriers have evolved in humans to maintain iron in a "soluble" state suitable for circulation in the bloodstream [i.e., bound to serum transferrin (Tf)] or to transfer it across cell membranes [through metal transporters such as divalent metal transporter 1 (DMT1) or ferroportin1/IREG1/MTP-1 (see below)] for tissue utilization. The capacity of readily exchanging electrons in aerobic conditions makes iron essential for fundamental cell functions, such as DNA synthesis, transport of oxygen and electrons, and cell respiration. In fact, iron deprivation threatens cell survival, and iron deficiency in humans is a serious public health problem throughout the world. In these pathological states, iron supplementation is the only therapeutic option. On the other hand, because humans have no means to control iron excretion, excess iron, regardless of the route of entry, accumulates in parenchymal organs and threatens cell viability. In fact, a number of disease states are pathogenetically linked to excess body iron stores, and iron removal therapy is an effective life-saving strategy in such circumstances. In every cell during its normal life in aerobic conditions, a small amount of the consumed oxygen is reduced in a specific way, yielding a variety of highly reactive chemical entities collectively called reactive oxygen species (ROS). Transition metal ions such as iron, having frequently unpaired electrons, are excellent catalysts, and play a decisive role in the generation of the very reactive species from the less reactive ones; for instance, by catalyzing the formation of hydroxyl radicals from reduced forms of O2. Therefore, the modulation of "free iron" availability and appropriate sequestration of iron is the main means by which cells keep ROS levels under strict control. In this vein, to avoid oxidative stress and cell damage, cells have developed systems to adjust intracellular iron concentration to levels that are adequate for their metabolic needs but below the toxicity threshold.
Iron homeostasis. More than two-thirds of the body's iron content (3-5 g in healthy adult humans) is incorporated into hemoglobin in developing erythroid precursors and mature red cells and depends on receptor-mediated endocytosis of diferric Tf bound to Tf receptors [Tf receptor 1 (TfR1)] (11). A new Tf receptor has been recently identified [Tf receptor 2 (TfR2)], which can bind diferric Tf but whose function and properties have not been completely understood (47). Fe2+ Tf binds to TfR1 on the surface of erythroid precursors; Fe2+ Tf/TfR1 complexes localize to clathrin-coated pits, which invaginate to form specialized endosomes. A proton pump decreases the pH within the endosomes, leading to conformational changes in proteins that result in the release of iron from Tf. The iron transporter DMT1 moves iron across the endosomal membrane to enter the cytoplasm (31). Meanwhile, apo-Tf and TfR1 are recycled to the cell surface, where each can be used for further cycles of iron binding and iron uptake. In erythroid cells, most iron moves into mitochondria, where it is incorporated into protoporphyrin to make heme. Because the erythron requires 20 mg of iron daily but only 1-2 mg of iron normally enters the body each day through the intestine, iron is recycled continually by breakdown of effete red cells in macrophages followed by iron loading onto serum Tf and delivery to bone marrow for reincorporation into red cells (21). Most of the remaining body iron, ranging from 0.5 to 1 g, is found in hepatocytes that store unutilized iron into specialized proteins [i.e., ferritin (Ft) and hemosiderin]. By contrast ~1-2 mg of iron are lost from the body each day by processes such as sloughing of skin and menstruation. This lost iron is replaced by absorption of dietary iron through the mucosa of the duodenum.
This simple model implies fundamental concepts that are key to understanding iron metabolism and its abnormalities in hemochromatosis (HC): 1) the erythron's requirement for iron is a priority and dominates body iron trafficking; 2) to assist hemoglobin synthesis, the release of reticuloendothelial (RE; macrophage) cell iron and iron loading onto circulating Tf is key; 3) duodenal epithelial cells must be informed of the erythron's needs and, possibly, of the state of body iron deposits. Although, in recent years, most of the effector proteins of iron uptake, transfer, and storage have been identified in discrete tissue (see also Table 1), the signals that orchestrate in a coordinate fashion the expression of these proteins and the relevant biochemical pathways that underlie the cross-talk between bone marrow, RE cells, and the intestine are still elusive.
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"Sensing" iron and controlling its trafficking at the cellular level. As discussed above, regulation of iron (and oxygen) levels in the cell are critical for cell survival or death. Consequently, sensing iron and oxygen and controlling their levels is vital for living organisms.
Very early in earth's history, in the absence of oxygen, elemental iron and sulfur could freely interact and assemble spontaneously. The iron-sulfur proteins, in which the iron is at least partially coordinated by sulfur, are found in a wide range of organisms from bacteria to man (7). In many of these proteins, the role of the cluster is to allow electron transfer, catalyze functions, or maintain structural integrity. Thus their chemical versatility and flexibility in catalytic and electron transfer reactions make them suitable for many fundamental functions (34). These clusters, particularly the 4Fe-4S clusters, have the capacity to accept or donate single electrons, they are frequently found in enzymes in which single electrons must be supplied or removed to catalyze transformations of substrate, as is the case in a number of mammalian respiratory chain proteins, such as succinate dehydrogenase, NADH dehydrogenase, and the cytochrome bcl complex. One major function of the Fe-S clusters, due to their chemistry, is sensing oxygen and iron. This is the case of the fumarate nitrate reduction protein (FNR) of Escherichia coli, an oxygen sensor, in which the loss of integrity of the cluster in the presence of oxygen is the key to sensing. In response to lowered oxygen tension, the metabolism of E. coli switches from use of oxygen to use of alternative terminal electron acceptors such as fumarate and nitrate, a change that requires the simultaneous transcriptional activation of over 50 genes of anaerobic metabolism (39). In the absence of oxygen, FNR binds to promoters of the genes of anaerobic metabolism and activates transcription. In the presence of oxygen, the cluster disintegrates, and the protein no longer binds DNA. Thus FNR provides a clear example in which a reactive iron-sulfur cluster is used to sense concentrations of the destabilizing agent, oxygen. What about sensing of iron? As mentioned, iron is essential for cell division and growth, but tight regulation of iron uptake and distribution is necessary because excess iron can be toxic, particularly because iron species and oxygen can interact to form ROS, including superoxide and hydroxyl radicals. Thus iron uptake and storage within most cells is carefully regulated by a set of genes that is highly conserved in mammalian cells to maintain an adequate substrate while also minimizing the pool of potentially toxic free iron. Proper sensing of iron and oxygen in the aerobic environment and the need for a tight control of iron and oxidants are also crucial for the cell to adapt to unfavorable and hazardous situations.The iron regulatory proteins sense iron and control proteins involved in iron homeostasis. Recent investigations suggest that a single genetic regulatory system, based on iron-sulfur interactions, senses iron and "orchestrates" all these aspects at the posttranscriptional level: the iron regulatory proteins (IRPs) (81). The IRPs represent the sensors of cytoplasmic iron and the controllers of the main proteins involved in iron homeostasis: Ft, TfR1, ferroportin1/Ireg1/MTP1, and the divalent metal transporter (DMT1; previously named Nramp2 and DCT1). These proteins are used by cells to adjust intracellular iron concentration to levels that are adequate for their metabolic needs but below the toxicity threshold. Ft and TfR1 hat have been found to contain at the untranslated region (UTR) of the mRNA noncoding sequences [i.e., the iron-responsive elements (IRE)] that are recognized by two cytoplasmic IRPs (IRP-1 and IRP-2). The IRPs belong to the aconitase superfamily: by means of an Fe-S cluster-dependent switch, IRP-1 can function as an mRNA binding protein or as an enzyme that converts citrate to isocitrate (43). Although structurally and functionally similar to IRP-1, IRP-2 does not seem to assemble a cluster or to possess aconitase activity; moreover, it has a distinct pattern of tissue expression and is modulated by means of proteasome-mediated degradation. In response to fluctuations in the level of the "free iron pool," IRPs act as key regulators of cellular iron homeostasis as a result of the translational control of the expression of a number of iron genes. Conversely, various agents and conditions may affect IRP activity, thereby modulating iron and oxygen radical levels in different pathobiological settings (15). Mammalian cells react to iron deficiency by presenting a higher number of TfR1 at the cell surface to internalize iron-laden Tf. At the same time, the synthesis of the iron storage protein Ft is halted to enhance metal availability. The opposite is true when iron overload occurs: TfR1 is downregulated to stop iron uptake, and Ft synthesis is increased to sequester excess iron in newly formed Ft shells. When iron is scarce, Ft and TfR1 mRNAs are specifically recognized and bound by the active form of IRP that blocks Ft translation (IRE at the 5' UTR of the mRNA) and stabilizes TfR1 mRNAs (IREs at the 3' UTR of the mRNA), respectively. On the contrary, when iron is abundant, IRPs are devoid of mRNA binding activity and target transcripts are freely accessible to translation complexes (Ft mRNA) or nucleases for degradation (TfR1 mRNA). IRPs therefore control cell iron status by means of divergent but coordinated regulation of iron storage (Ft) and uptake (TfR1). Interestingly, the UTR of mRNA for important putative iron import and export proteins also carries IREs. Three groups have isolated and characterized the product of the SLC11A3 gene referred to as ferroportin1/IREG1/MTP1 (1, 25, 57). The protein product is a putative multiple membrane-spanning transporter that has been shown to function as an iron exporter. The localization of Ferroportin1/Ireg1/MTP1 in cells and tissues is consistent with its proposed function of exporting iron from cells. The protein is found in the liver, predominantly in Kupffer cells (1, 25), and on the basolateral membrane of polarized cells (25, 57). The Ferroportin1/IREG1/MTP1 mRNA possesses an iron-responsive element in the 5' UTR that binds IRPs and confers iron-dependent regulation of luciferase in desferoxamine-treated COS7 cells (1). However, the protein levels found in vivo under varying conditions of iron repletion are not entirely consistent with this type of regulation. Immunohistochemical staining for the iron exporter revealed strong reactivity in the Kupffer cells of iron-replete mice with weaker staining in iron-depleted mice, consistent with regulation through the IRPs (57). However, the reciprocal result was found in the duodenal epithelium; immunohistochemical staining was strong in iron-depleted mice and weaker in iron-replete mice (57).
Functional IREs are also present in one of the two isoforms (i.e., the isoform that is predominant in the intestine) of the DMT1/Nramp2 (38, 73). DMT1 function and regulation have been reviewed recently (4). DMT1 is a proton symporter that transports ferrous iron and other divalent metals from the intestinal lumen into the enterocyte or from the endosomes to the cytoplasm in erythroid cells and other cell types (32, 40). The IRE is at the 3' UTR of the DMT1 mRNA, which suggests that low iron would stabilize the mRNA, as in the case of TfR1 mRNA. Paradoxically, the mRNA coding for the long-awaited protein in iron metabolism, the HC gene product HFE, does not contain IREs nor is it known to be regulated by iron status. Yet, as discussed below, HFE has a dramatic impact on cell iron trafficking and, indirectly, on intestinal iron absorption.The HC (HFE) gene product binds TfR1.
HC represents one of the most common single-gene hereditary diseases
(3). A cornerstone of HC genetics was laid in 1996, with
the isolation of the HC gene, now called HFE (26). The majority of HC patients carry the same mutation, resulting in a change
from cysteine at position 282 to tyrosine (C282Y) in the HFE
protein (59). The human HFE protein is closely
related to the major histocompatibility complex (MHC) class I
molecules. The C282Y mutation disrupts a critical disulfide
bond in the 3-domain of the HFE protein and abrogates
binding of the mutant HFE protein to
2-microglobulin
(
2-M) (28). This results in reduced
transport to and expression on the cell surface (90).
Conversely, mice lacking
2-M show a hemochromatotic
phenotype (84). The HFE knockout and knockin (carrying
only the C282Y mutation) mice recapitulate the human disease (54,
93).
The free iron pool and the IRPs control cell iron import, storage,
and export.
In the simple scheme depicted above involving proteins devoted to iron
uptake, transfer, store, and release, the IRP system may be used by the
cell to sense iron and to efficiently coordinate its
trafficking. However, as demonstrated in other settings,
protein of iron metabolism, including Ft and TfR, may undergo
additional regulatory mechanisms through transcriptional and
posttranscriptional pathways depending on the specific cell context
(15). In fact, ferroportin1/IREG1/MTP1 is also controlled
at the level of mRNA accumulation in the hypotransferrinemic mice
(58) or intracellular protein trafficking
(1). Similarly, DMT1 subcellular localization has been
also found to vary in the duodenum according to the iron status in
iron-loaded or -depleted rats (88). In general, it is the
fluctuation of the intracellular iron pool, through the IRP system or
directly through transcriptional/posttranscriptional controls, that
signals the complex genetic machinery controlling iron homeostasis.
This may be true for epithelial cells devoted to absorption or storage
of iron or mesenchymal cells involved in iron recycling. In different
cell types, the system may operate in different ways depending on the
relative function of the target protein in the particular cell. For
instance, rapidly growing cells (e.g., stem cells in the intestinal
crypts) or erythroid cells depend exclusively on TfR expression to
provide iron for growth or hemoglobin synthesis, respectively. Most
likely, they do not need iron-export systems. On the other hand, liver
parenchymal cells are used as "storage" cells; they are relatively
quiescent and express very little TfR under normal conditions and none
during iron overload (71). In the hepatocytes, iron is
stored in Ft that is able to accommodate 4,500 atoms of iron per
molecule. When needed, hepatocytes export iron, possibly through
ferroportin1/IRG1/MTP1, and may load circulating Tf to meet bone marrow
needs. During iron overload, when TfR1 is further downregulated in the
liver (71), a non-Tf bound form of iron appears in the
bloodstream, which is taken up by the hepatocytes through mechanisms
different from that of Tf-bound iron (13). In addition,
the recently described TfR2 (47), which is capable of
delivering Tf iron, appears to be normally expressed during liver iron
overload (33). These mechanisms ensure that the liver
serves as a physiological sink for iron during iron overload states
(see also Fig. 1).
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The "free iron pool" and the IRPs control intestinal iron absorption. In polarized cells involved in iron extraction from the external milieu (syncytiotrophoblasts in the placenta and epithelial cells in the duodenum) iron-protein expression and regulation is instrumental to the specific role of the cell.
In intestinal cells, iron must be transferred across two lipid bilayers: the apical and the basolateral membrane. In addition, a vertical functional axis exists in the intestinal villus, where cells at the tip or at the bottom (crypts) of the villus have a completely different pattern of expression of iron carriers and, consequently, a different role in iron transport. Within the crypts of the intestine are multipotent precursor cells, actively proliferating and expressing TfR1, which eventually migrate onto the villus and differentiate into absorbing enterocytes. (44, 75). Crypt cells do not absorb dietary iron; in fact, they do not express appreciable amounts of the apical iron transporter DMT1 (17) or the basolateral transporter ferroportin (25, 57). However, seemingly to erythroid precursors, they avidly import iron from the circulation through a highly efficient TfR1-driven iron-uptake system, and all iron is retained by the cell to fulfill high growth demands. Iron not used to sustain growth may be stored into Ft and reaches, as such, the higher portion of the villus after maturation-differentiation of the enterocytes. The mature enterocytes of the villus are specialized for absorption and transport of dietary iron (Fig. 1). Indeed they are equipped with iron carriers and coupled reductase or ferroxidase activities at the apical and basolateral membrane. Dietary free iron first undergoes reduction from the ferric (Fe3+) to the ferrous (Fe2+) state on the luminal surface of the proximal small intestine through the recently discovered duodenal cytochrome b (Dcytb) (56). Dcytb is probably the protein responsible for iron reduction at the brush border of enterocytes, because antibodies against Dcytb are able to block intestinal ferric reductase activity (56). Once reduced, iron is transported into the enterocytes by the apical transporter DMT1 (4). Iron can also be absorbed by the heme-iron uptake pathway that functions as a very efficient means of iron uptake, but the molecular mechanisms of transport into or across the intestinal epithelium have not yet been elucidated. Finally, a mucin-integrin-mobilferrin pathway has also been postulated as a possible means of iron uptake (20). Once in the enterocyte, iron may be stored within the cell as Ft and lost with exfoliation of the intestinal epithelium (36) or transferred across the basolateral membrane to the plasma, possibly by the transport protein ferroportin1/Ireg1/MTP1. Hephaestin (89), a ceruloplasmin-like molecule, may assist the transfer of iron to the plasma through the oxidation of Fe2+ to Fe3+. Hephaestin is the gene mutated in the sex-linked anemia (SLA) mice, in which efflux of iron through the basolateral membrane and into the plasma is inhibited. Hephaestin expression is restricted to cells of the villus, sparing crypt cells, and is associated to membranes (cell membrane and/or membrane vesicles) (50). Although hephaestin certainly plays a crucial role in iron efflux from the enterocyte, the actual transporter that shares the iron efflux pathway with hephaestin is not yet known. Ceruloplasmin, itself, has ferroxidase activity, and is involved in the release of iron from cells and, possibly, in loading iron onto circulating Tf (41, 63, 66). Accordingly, patients with aceruloplasminemia have accumulation of iron in neural and glial cells of the brain (particularly the basal ganglia and dentate nucleus), hepatocytes, and pancreatic islet cells (42). Within this framework, the most likely hypothesis is that the free iron pool within the mature enterocyte is the key regulator of iron absorption. In early studies, it was suggested that this iron pool dictates, through IRPs and additional transcriptional and posttranscriptional mechanisms, the level of expression of the apical and basolateral iron transporters and iron transfer through the enterocyte (69, 70). Because the compartment of the differentiated iron-absorbing enterocytes (devoid of TfR-HFE) is functionally "isolated" from the compartment of body iron and unable to be informed of the body iron status, it is the iron status determined in the precursor crypt cells (enriched in TfR-HFE) that eventually "transfer" the information on body iron status to the mature enterocytes (Fig. 1). This was shown in early studies using 59Fe in animal and following the radioactivity in the enterocytes as they ascend the villus during the life cycle (24). In accordance with this model, it has been shown that duodenal IRP activity was inversely related to body iron status, being elevated in anemia and decreased in iron overload, which also implied that the iron pool of the enterocyte was low or high, respectively, in these conditions (69). Accordingly, the expression of TfR in the crypts is inversely related to iron stores (2, 76). If true, the apical and basolateral iron transporters should be up- and downregulated depending on iron and IRP status. Indeed, DMT1 and ferroportin activity have been reported to be increased in iron-deficient subjects and decreased in iron overload, suggesting that intestinal iron status may set the level of expression of iron transporters and, possibly, of their activity (94). One important addition to our understanding of iron homeostasis comes from the observation made in the hypotransferrinemic mice (gene symbol hpx). Homozygous hpx mice die from severe anemia early in life due to deficiency in serum Tf (9). A similar phenotype is found in human atransferrinemia (9). Anemia is due to inability to provide iron to erythroid precursors. This proves the importance of Tf (and TfR) for erythropoiesis. On the other hand, the hpx mice develop severe tissue iron overload due to increased iron absorption and delivery of non-Tf-bound iron to tissues. This indicates that 1) Tf (and TfR) is not essential for iron uptake in nonhematopoietic cells, 2) it is not directly involved in intestinal iron absorption, and 3) signals originating in the "erythron" are able to greatly enhance iron absorption despite body iron overload.Sensing iron and controlling its trafficking at the BODY level.
It is generally believed that the enterocyte receives signals from
various tissues as to the relative repletion of iron stores. This
regulatory mechanism of iron absorption is termed the "stores regulator" (29). When the amount of iron found in body
stores drops below a critical level, the stores regulator increases
iron uptake until the reserves are replete again (23, 35,
45). The opposite is true during iron overload. The stores
regulator acts on a pathway that facilitates a slow accumulation of
nonheme dietary iron (~1 mg/day) (85) and is able to
change iron absorption rate to a limited extent. It has been postulated
that soluble components might serve as store regulators: serum Ft, Tf,
or the serum (soluble) TfR (29). Recently, a new candidate
has been put forth: hepcidin. Two groups searching for novel
antimicrobial peptides independently discovered hepcidin. Krause et al.
(49) purified the peptide from human blood (designating it
liver-expressed antimicrobial peptide). Park et al. (67)
isolated it from human urine, designating it hepcidin (hepatic
bactericidal protein). Expression of hepcidin mRNA was nearly confined
to the liver. The transcript encodes a precursor protein of 84 amino
acids, including a putative 24-amino acid leader peptide, whereas the circulating form consists of only the COOH-terminal 25 amino acids. Due
to significant antibacterial and antifungal activities of the
COOH-terminal peptide, hepcidin was classified as a member of the
cysteine-rich, cationic, antimicrobial peptides, including the thionins
and defensins (52). Nicolas et al. (64) found that mice developed iron overload consequent to targeted disruption of
the gene encoding the transcription factor upstream stimulatory factor
2 (USF2). In the USF2 knockout mice, the
character of iron overload resembled that of human HC. Specifically,
the hepatic iron distribution is predominantly periportal, whereas the
RE system is relatively spared from iron loading. In attempting to explain these findings, the investigators discovered that
USF2 knockout mice fail to express either copy of the
duplicated hepcidin genes immediately downstream of USF2,
leading them to attribute the iron loading to absence of hepcidin. A
link between hepcidin and iron homeostasis had been previously made by
Pigeon et al. (72), who independently cloned the
orthologous murine cDNA by differential screening for hepatic mRNAs
overexpressed with iron overload. Northern blots confirmed that
hepcidin mRNA is increased with dietary iron loading and also increased
in 2-M knockout mice. No iron-responsive elements were
identified in the hepcidin transcript, so the mechanism for the change
in mRNA content with change in iron status was unclear. This
observation, coupled with the phenotype of the USF2 knockout
mice, may lead to suggest a possible role for hepcidin in controlling
iron homeostasis during inflammation and ACD: high hepcidin level would
induce sequestration of iron in RE cells and downregulation of
intestinal iron absorption. Nicolas et al. (64) speculated
that TfR-2 mediates iron uptake by hepatocytes, which, in turn,
modulates expression of hepcidin, which, in turn, interacts with
HFE-TfR1 in the duodenal crypt cell to regulate dietary iron
absorption. However, still some caution must be used, because, as also
pointed out by Nicolas et al. (64), it is possible that
changes in expression of another gene on disruption of USF2
led to the observed phenotype.
HC: a disorder of the "store's regulator." Iron absorption is inappropriate to body iron stores in HC and steadily increases from birth despite expanding iron deposits (12). Typically, in HC subjects, there is a positive iron balance of 1-2 mg of iron daily that during childhood and adolescence in male and in menstruated females does not cause marked iron accumulation due to high growth demands and iron losses, respectively. Afterwards, iron overload in the liver, pancreas, heart, and joints leads to cell damage and organ disease. After phlebotomy, as in normal subjects, a sharp increase in intestinal iron absorption occurs in HC. However, at variants with nonhemochromatotic subjects, iron absorption remains at a high rate for a long period of time (86). This indicates that the absorption machinery is intrinsically normal in HC, whereas the feedback control from body stores is lost. In HC, the store's regulator may be unable to signal the intestine or fails to "see" the expanding iron store and interpret it as iron deficiency.
In view of the available data, any proposed model of HFE function in iron metabolism has to consider 1) the biochemical evidence (i.e., HFE interacts with TfR1), 2) the pattern of expression of TfR1 and HFE in vivo, and 3) the phenotype of human HC. At the biochemical level, data from several tissue culture studies show that overexpression of HFE results in significant reduction in the rate of iron uptake, decrease in iron and Ft, and induction in TfR1 expression (22, 37, 46, 80, 82, 83). The proposed mechanism of TfR inhibition by HFE is controversial. Initial studies (82) indicated that HFE does not reduce Tf uptake at saturating Tf concentrations or alter the cycling of the TfR1. Others showed a reduction in Tf uptake (83) or a reduction in the rate of Tf recycling to the cell surface (46). Some caution should be used in extrapolating these in vitro data to the in vivo situation. Most of these studies have been carried out in vitro using concentrations of Fe2+ Tf that is lower that that found in plasma (8-15 µM) or using bovine serum Tf, which has a low affinity for human TfR1, or expressing inappropriately and nonphysiological levels of HFE. It is in fact clear that the stoichiometry of Tf, HFE, and TfR1, and their relative equilibrium in the cell may be critical in determining a biological effect. Studies of HFE and TfR1 in transfected cells and in solution suggest that stoichiometry is 1:2, or one HFE per Tf-receptor dimer (37, 51). However, the crystal structure indicates that a 2:2 stoichiometry is also possible under very high concentrations of HFE (~8 nM) (8). The relative concentrations of HFE and TfR1 appear to be important also in vivo. Mice lacking HFE (or having the human HC C282Y HFE allele) and one TfR allele show more iron loading than HFE knockout mice (53). HFE is mainly expressed in intestinal crypt cells and macrophages of the liver (Kupffer cells) in tissue-staining experiments with specific antibodies (6, 68). TfR1 appears to be highly expressed in the crypts (55). Although macrophages are believed to express low TfR1 and phagocytosis of erythrocytes accounts for the majority of iron acquired by these cells in vivo, TfR1-mediated uptake may also occur in culture (87) and in vivo (10) in macrophages. Therefore, judging from the results of the available studies, the relative equilibrium of HFE to TfR1 in duodenum and macrophages may be different in vivo, and this may have reflection on the function in the relevant tissue. In one of these studies, the expression of HFE in Kupffer cells of the liver was particularly strong (6), and this might indicate a special role of HFE in these cells. In summary, although the in vitro observations did lead to the hypothesis that the function of HFE in vivo is to inhibit TfR1-mediated iron-Tf uptake, there are concerns due to intrinsic limitations of the in vitro approach. Moreover, the in vitro findings do not explain the HC phenotype: a mutated HFE should lead to iron overload, whereas in HC, tissues with the strongest HFE (and TfR1) expression are actually iron deficient (i.e., crypt cells and macrophages). In fact, in HC patients (14) and in murine models of HC (i.e., HFE and ![]() |
ACKNOWLEDGEMENTS |
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I thank Dr. C. Garuti for assistance and helpful discussion.
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FOOTNOTES |
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Address for reprint requests and other correspondence: A. Pietrangelo, Dept. of Internal Medicine, Policlinico, Via del Pozzo 71, 41100 Modena, Italy; (E-mail: pietrangelo.antonello{at}unimo.it).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
10.1152/ajpgi.00404.2001
Received 13 September 2001; accepted in final form 8 November 2001.
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