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Blood, 15 December 2000, Vol. 96, No. 13, pp. 4020-4027
REVIEW ARTICLE
Iron homeostasis: new tales from the crypt
Cindy N. Roy and
Caroline
A. Enns
From the Department of Cell and Developmental Biology,
Oregon Health Sciences University, Portland, OR.
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Abstract |
The enterocyte is a highly specialized cell of the duodenal
epithelium that coordinates iron uptake and transport into the body.
Until recently, the molecular mechanisms underlying iron absorption and
iron homeostasis have remained a mystery. This review focuses on the
proteins and regulatory mechanisms known to be present in the
enterocyte precursor cell and in the mature enterocyte. The recent
cloning of a basolateral iron transporter and investigations into its
regulation provide new insights into possible mechanisms for iron
transport and homeostasis. The roles of proteins such as iron
regulatory proteins, the hereditary hemochromatosis protein
(HFE)-transferrin receptor complex, and hephaestin in regulating this
transporter and in regulating iron transport across the intestinal
epithelium are discussed. A speculative, but testable, model for the
maintenance of iron homeostasis, which incorporates the changes in the
iron-related proteins associated with the life cycle of the enterocyte
as it journeys from the crypt to the tip of the villous is proposed.
(Blood. 2000;96:4020-4027)
© 2000 by The American Society of Hematology.
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Introduction |
Iron is required by almost every organism.
The ability of this transition metal to exist in 2 redox states makes
it useful at the catalytic center of fundamental biochemical reactions. DNA synthesis, transport of oxygen and electrons, and respiration all
require iron. The same properties that make iron useful in each of
these reactions also make it toxic. Free iron has the ability to
generate oxidative radicals that damage essential biologic components
such as lipids, proteins, and DNA. An organism must sense its internal
iron load and respond appropriately by altering iron uptake and storage
processes. In the case of humans, the amount of iron that is absorbed,
rather than the amount that is excreted, is controlled. Inappropriate
responses or lack of a response lead to anemia or iron overload.
The most important checkpoint of iron homeostasis in higher organisms
is contained in the epithelial cell layer of the duodenum, which is
responsible for sensing changes in body iron demands and then adapting
to meet them. Within the crypts of the intestine are multipotent
precursor cells, some of which migrate onto the villus and
differentiate into enterocytes.1,2 The enterocytes are
specialized for absorption and transport of iron (Figure
1). The precursor cells differ from
enterocytes in their expression of proteins related to iron uptake and
transport 3-7 (Figure 2).
Although its precursor acts only as a sensor of body iron needs, upon
differentiation the enterocyte is capable of transporting iron. New
proteins required for the absorption, storage, and export of the total
dietary iron requirement of the organism are expressed in the
enterocyte.
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| Figure 1.
Life cycle of the duodenal enterocyte.
Stem cells present in the crypts of the duodenum proliferate and give
rise to precursor cells that further differentiate into absorptive
cells or enterocytes. These enterocytes are highly specialized for
absorption of micronutrients from the intestinal lumen. Their apical
membrane is structured with microvilli and contains enzymes that
facilitate transport of nutrients through the epithelial cell layer.
The majority of iron absorption is facilitated by these specialized
cells. The process of differentiation occurs simultaneously with
migration out of the crypt and onto the villus. Zones of cells in
similar stages are evident when the crypt/villus junction is viewed in
cross section. After the cells have migrated to the villar tip, they
are exfoliated and excreted.
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| Figure 2.
A model for the establishment of the enterocyte iron
absorptive set point in the crypt.
Precursor cells (left) present in duodenal crypts express a complement
of iron metabolic proteins that are distinct from those of the
differentiated enterocyte (right). In the crypt, the transferrin
receptor (TfR)-HFE complex facilitates iron uptake from transferrin
(Tf) in the plasma and contributes to the labile iron pool. The labile
iron pool directly influences iron regulatory protein RNA binding
activity and may affect iron-regulated transcription, translation,
protein trafficking, and degradation processes. In this way, the iron
absorptive capacity, or set point for the enterocyte, may be
established in the crypt. When the precursor cell differentiates, the
expression of proteins specific to the enterocyte, such as the apical
and basolateral iron transporters and hephaestin, is induced. Although
the enterocyte precursor absorbs, but does not transport iron, the
differentiated enterocyte takes up iron from the duodenum at the apical
membrane through the divalent metal transporter (DMT1) and transports
it into the plasma. The basolateral iron transporter,
Ferroportin1/Ireg1/MTP1 (F/I/M), has been shown to act independently as
an iron exporter. The multicopper oxidase, hephaestin, is also required
for efficient iron efflux from the enterocyte, but whether it acts
through Ferroportin1/Ireg1/MTP1 or another pathway is not yet
known.
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Regulation of iron uptake into the body occurs at 2 interfaces of the
intestinal epithelium: the apical and basolateral membranes. The apical
membrane of the differentiated enterocyte, which faces the intestinal
lumen, is specialized for transport of heme and ferrous iron into the
cell. At least 3 pathways have been observed for this transport
process. The most extensively characterized uptake pathway is via the
divalent metal transporter, DMT1 (previously named Nramp2 and DCT1).
The DMT1 sequence,8,9 function,10-17 and
regulation 6,18-20 have been reviewed
recently.21,22 DMT1 is a proton symporter that transports
ferrous iron and other divalent metals from the intestinal lumen into
the enterocyte.10-12 Its expression is regulated by body
iron stores,11,19 but it may also be susceptible to
regulation by dietary iron,23,24 or through a recently
observed posttranslational mechanism.20 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.25-27 Finally, a mucin-integrin-mobilferrin pathway has also been identified as a possible means of iron
uptake.28
The basolateral membrane mediates the transfer of the iron transported
into the intestinal epithelial cells to the rest of the body. Iron that
is not exported into the plasma is lost with exfoliation of the
intestinal epithelium.2,29,30 The proteins related to iron
metabolism on the basolateral membrane of the precursor and mature
enterocyte either sense body iron stores, or facilitate regulated iron
transport into the plasma. These include the transferrin
receptor-hereditary hemochromatosis protein (HFE)
complex,31-33 the basolateral iron
transporter,7,34,35 and the ceruloplasmin homologue,
hephaestin.5 Although the transferrin receptor
structure,36 function,37,38 and
regulation39 have been well described, the remaining
proteins have only recently been identified. Advances toward the
understanding of their individual function and regulation are the
subjects of this review.
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Communication and regulation |
The enterocyte receives signals from various tissues as to the
relative repletion of iron stores. Although none have been clearly
identified, several "regulators" for iron homeostasis have been
hypothesized, based on the segregation of iron requirements within an
organism. When the amount of iron found in body stores such as the
liver, skeletal muscle, and blood drops below a critical level, the
stores regulator increases iron uptake until the reserves are replete
again.40-43 The stores regulator acts on a pathway that
facilitates a slow accumulation of nonheme dietary iron (about 1 mg/d).44 It does not seem to significantly regulate
heme-iron uptake.27,43,45 The stores regulator also has
the important task of preventing iron overload after ensuring iron
needs are met. It reconditions the intestinal epithelium such that iron absorption is reduced in the face of enlarged iron stores, and it
reduces the average uptake of iron per day in adulthood when growth
requirements decrease.46 Because this regulator must signal between the liver, muscle, and intestine, a soluble component is
hypothesized. Serum ferritin,47,48
transferrin,48,49 and the serum transferrin receptor
50,51 have all been proposed as candidate molecules.
The erythropoietic regulator is a second hypothesized regulator of iron
absorption that communicates the erythropoietic demand of the organism
rather than directly reflecting iron stores. In support of this
hypothesis, individuals with normal, or even increased, iron stores
up-regulate iron absorption as marrow iron requirements increase.46,52 An increase in erythropoiesis alone is not
enough to increase iron absorption. Rather, the imbalance between the rate of erythropoiesis of the marrow and its iron supply is thought to
induce iron absorption.52-54 The absorptive pathway
targeted by the erythropoietic regulator is probably distinct from the pathway targeted by the stores regulator, as evidenced by the rate of
iron uptake. Anemic individuals can absorb between 20 and 40 mg of iron
per day: an increase much greater than that which the stores regulator
is capable of producing.46 Like the stores regulator, the
erythropoietic regulator is hypothesized to be a soluble component of
the plasma, as it must signal between the erythroid marrow and the
intestine.55
Recent insights into the regulation of the machinery required for iron
absorption have confirmed earlier hypotheses that hypoxia may play a
role as an independent regulator that induces intestinal iron
absorption.34,56,57 Whether this regulatory pathway is truly distinct from the one induced by the erythropoietic regulator is
uncertain. The signaling pathways and molecular components involved in
the up-regulation of iron absorption through any of these regulators
remain to be determined.
The stores and erythropoietic regulators are humoral factors that
maintain iron homeostasis for the entire organism. Other regulatory
mechanisms are in place for the maintenance of iron homeostasis for a
single cell. Briefly, iron regulatory elements (IREs) are stem loop
structures in the 3' or 5' untranslated region of several key messenger
RNA (mRNA)-encoding proteins of iron metabolism. Iron responsive
proteins (IRPs) work in conjunction with these elements to sense and
respond to changes in the amount of chelatable iron in the
intracellular environment, or the "labile iron pool." Through the
interaction of IRPs with IREs, transferrin uptake increases by
stabilizing the transferrin receptor mRNA, whereas ferritin storage of
iron decreases by blocking translation of ferritin mRNA. These events
result in an increase in the labile iron pool. Conversely, transferrin
uptake decreases and ferritin levels increase when intracellular iron
concentrations rise. The reciprocal regulation of these 2 proteins has
been extensively reviewed for nonpolarized cells
elsewhere.58,59
The labile iron pool of the enterocyte appears to regulate a subset of
proteins involved in iron homeostasis. Transferrin receptor expression
in duodenal crypts responds to increases or decreases in body iron
stores.60-63 Similarly, duodenal ferritin levels decrease
with the increased transfer of iron to the plasma.63 Much
attention has been focused on the role of IRPs in the modulation of
enterocyte-specific iron transport proteins, especially proteins with
IRE containing messages such as DMT111,18 and the newly identified basolateral iron transporter,
Ferroportin1/Ireg1/MTP1.7,34,35 DMT1 has an IRE in the 3'
untranslated region of its message, suggesting it would be degraded,
like the transferrin receptor message, in the context of a high labile
iron pool. Ferroportin1/Ireg1/MTP1 has an IRE in the 5' untranslated
region of its message, suggesting it would be translated more
efficiently, like the ferritin message, in the context of a high labile
iron pool. Experiments designed to test for the control of DMT1 and
Ferroportin1/Ireg1/MTP1 by IRPs11,18,34,35 have suggested
other regulatory mechanisms may be involved in addition to regulation
through IRPs. Although the labile iron pool and IRPs influence iron
transport across the enterocyte,64-66 other forms of
regulation through the labile iron pool such as iron-regulated
transcription,67,68 degradation,69,70 and
intracellular trafficking events20,35 could also be involved.
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The HFE-transferrin receptor complex |
HFE-associated hereditary hemochromatosis is a disorder of
enterocyte iron regulation characterized by increased dietary iron uptake and resulting in iron overload. Although an increase in transferrin saturation may be observed within the first 2 decades, the
complications due to iron overload usually do not present until the
fourth or fifth decade of life.71 The defect has been described as an increase in the iron regulatory "set
point"42 because affected individuals experience a
chronic increase in the rate of iron transfer from the enterocyte to
the blood.72 The hereditary hemochromatosis defect has
been attributed to a decrease in the amount of functional HFE
protein.31,73-78
The first indication of how HFE might regulate iron metabolism came
with the discovery that it associates with the transferrin receptor.32,33,79-82 The transferrin receptor is expressed
at the cell surface and binds the serum iron transport protein,
transferrin, with high affinity. Transferrin releases iron in endosomes
following their acidification, after which the iron is transported
across the endosomal membrane and targeted for use in iron containing enzymes, or for storage in ferritin.37,38 HFE binds
transferrin receptor with an affinity close to that of transferrin,
reducing the affinity of the transferrin receptor for transferrin and
competing with transferrin binding.33,80,81,83
The close association of HFE with the transferrin-mediated iron uptake
pathway84-86 and its location in endosomes81
and on the basolateral side of enterocyte precursor cells87
(Figure 2) implicates a role for HFE in sensing body iron stores.
Transferrin48,49 and the serum transferrin
receptor,50,51 2 proteins with which HFE may directly
interact, have both been hypothesized as stores regulators. The
mechanism by which HFE might facilitate the sensing of body iron stores
remains unknown, however. Alternatively, the role of HFE in
establishing the set point for iron transport may be independent of
body iron stores. HFE-deficient mice are capable of changing the
rate of dietary iron uptake with changes in body iron
stores.77,88
Indirect evidence implies that the relative concentrations of HFE and
transferrin receptor are important in iron loading in mice. An elegant
study used the HFE and transferrin receptor knockout mice to determine
the relative contributions of these 2 proteins to iron loading. The
authors found that mice lacking HFE and one transferrin receptor allele
experienced more iron loading than that of HFE knockout mice. The same
trend was seen with the mice that have the human hemochromatosis C282Y
HFE allele and only one transferrin receptor allele.89
Because mice with only one copy of transferrin receptor cannot increase
transferrin receptor levels to those of wild-type mice,90
this result suggests that the ratio between HFE and transferrin
receptor is critical for the maintenance of iron homeostasis. The
actual HFE:transferrin receptor stoichiometry is not clear, nor are the
relative amounts of each protein in intestinal precursor cells. Studies
of HFE and transferrin receptor in transfected cells and in solution suggest the stoichiometry is 1:2, or one HFE per transferrin receptor dimer.80,81 However, the crystal structure indicates a 2:2 stoichiometry is also possible under very high concentrations of HFE
(approximately 8 mmol/L).82 Although the iron-loading results of the compound HFE / and transferrin receptor+/ knockout mice are informative, they must be interpreted cautiously. The HFE
knockout mice with only one transferrin receptor allele also have
iron-deficient erythropoiesis. The compound knockout mice may take up
more iron than the HFE knockout mice because of the response of the
erythroid regulator rather than the stores regulator.89
Surprisingly, overexpression of HFE in cells grown in culture reduces
iron uptake and lowers intracellular ferritin
levels.81,84-86 This result was initially unexpected
because the enterocytes of individuals with hereditary hemochromatosis,
who possess little or no functional HFE, appear to have lower ferritin
levels than healthy individuals.91 Although the effect on
intracellular ferritin is a universal finding, the mechanism by which
this might be accomplished is more controversial. Initial studies
established that HFE does not reduce transferrin uptake at saturating
transferrin concentrations or alter the cycling of the transferrin
receptor.84 Other reports attributed differences in iron
uptake to a reduction in transferrin uptake92 or a
reduction in the rate of transferrin recycling to the cell
surface.93
Consistent with its effect on ferritin and transferrin-receptor
regulation,81 HFE has been shown to increase the RNA
binding activity of IRPs.85,86 The involvement of IRPs is
of great interest because of their seemingly universal control over
cellular iron regulation, including pathways of iron uptake, storage,
and utilization.39,58 IRPs are functional in individuals
with hereditary hemochromatosis in that they can respond to
fluctuations in iron levels.94,95 These results suggest
that IRP RNA binding activity, though necessary, is not sufficient for
the maintenance of iron homeostasis in an individual. Whether HFE has
direct effects on IRP RNA binding activity as do protein kinase C and
nitric oxide, or whether HFE increases IRP RNA binding activity
indirectly through a reduction of the labile iron pool, remains to be
seen.96-98
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Ferroportin1/Ireg1/MTP1 |
An exciting addition to our understanding of iron metabolism has
come with the cloning and characterization of a putative basolateral
iron transporter. Several groups have used multiple systems by which to
isolate and characterize the gene referred to as
Ireg134 or MTP135 in mice
and weissherbst (weh) in zebrafish.7 The
protein product is a putative multiple membrane-spanning transporter that has been shown to function as an iron
exporter.7,34,35 Two of the aforementioned studies used a
Xenopus oocyte expression system to characterize iron export
in oocytes expressing Ferroportin1/Ireg1/MTP1.7,34 Both
groups coexpressed DMT1 to load oocytes with iron and then assayed for
iron efflux in the presence of apotransferrin. One study also indicated
that ceruloplasmin was necessary for iron efflux, whereas
apotransferrin was not. These results are consistent with the ability
of hypotransferrinemic mice to facilitate mucosal iron transfer,
despite the lack of transferrin expression.34,99
The localization of Ferroportin1/Ireg1/MTP1 in cells and tissues is
consistent with its proposed function of exporting iron from cells. In
the duodenum, Ferroportin1/Ireg1/MTP1 localizes to mature enterocytes
and is absent from the crypts7,34,35 (Figure 2). The
protein is also found in the liver, predominantly in Kupffer cells
where iron is scavenged from red blood cells, but some immunostaining
also localizes to the hepatocytes.7,35 The specific
intracellular localization of Ferroportin1/Ireg1/MTP1 in polarized
cells is on the basolateral membranes of placental trophoblasts7 and MDCK cells overexpressing the
transporter.34
Investigations aimed at understanding the regulation of this iron
exporter have identified several potential levels of regulation. The
Ferroportin1/Ireg1/MTP1 mRNA possesses an iron-responsive element in
the 5' untranslated region that binds IRPs.7,34,35 This
stem loop structure is similar to other iron-responsive elements found
at the 5' end of mRNAs encoding ferritin, erythroid 5-aminolevulinate synthase, mitochondrial aconitase, and succinate
dehydrogenase.34 The protein products of these messages
are not translated under low iron conditions because of the binding of
IRPs, suggesting Ferroportin1/Ireg1/MTP1 would be down-regulated under
the condition of low intracellular iron.58 Although this
stem loop structure confers iron-dependent regulation of luciferase in
desferoxamine-treated COS7 cells35 and binds
IRPs,34,35 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. However, the reciprocal result was found in the
duodenal epithelium; immunohistochemical staining was strong in
iron-depleted mice and weaker in iron-replete mice.35
Other levels of regulation must also exist because the
Ferroportin1/Ireg1/MTP1 message is increased in the duodenum of
hypotransferrinemic mice.34 If translational control of
protein synthesis was the only mode of regulation, message levels
should not fluctuate. Up-regulation of the message was also observed
under hypoxic conditions.34 A hypoxic response is in
keeping with some studies that have observed a connection between the
erythroid regulator and the mucosal oxygen supply in regulation of iron
uptake.100,101 The rapid loading of hepatic iron stores in
the hypotransferrinemic mice99 to levels above those of the
HFE knockout mice77,78 implicates up-regulation of pathways
that can increase iron uptake many times that of the stores regulator,
such as that induced by the erythroid regulator.46 As
hypotransferrinemic mice suffer severe anemia,49,99 either
an erythropoietic or a hypoxic response may be the mechanism by which
the Ferroportin1/Ireg1/MTP1 message is up-regulated in the
hypotransferrinemic mice. In fact, transfusion of these mice with
erythrocytes of wild-type littermates reduced transfer of iron across
the basolateral membrane without changing iron uptake across the apical
membrane.49,102 Although specific iron transporters were
not addressed by these experiments, the data suggest that apical iron
uptake may be unaffected by alleviation of anemia, but that transport
of iron across the basolateral membrane was down-regulated with an
increase in hematocrit. These results are consistent with what we now
know concerning regulation of DMT1 and Ferroportin1/Ireg1/MTP1.
Although DMT1 regulation would not be expected to change rapidly,
Ferroportin1/Ireg1/MTP1 activity would be expected to diminish with an
increase in hematocrit and the subsequent increase in oxygen delivery.
Recent findings argue for additional Ferroportin1/Ireg1/MTP1 regulation
at the level of protein trafficking. Abboud and Haile35 observed that this exporter has significant intracellular localization in enterocytes of iron-replete mice, whereas iron-depleted mice have
more pronounced localization of Ferroportin1/Ireg1/MTP1 to the
basolateral membrane.35 Similarly, an iron-dependent
regulation of DMT1 subcellular localization has been observed in the
duodenal epithelium. In this case, control and iron-loaded rats showed predominant staining of DMT1 in intracellular sites of the enterocyte, whereas iron-depleted rats showed predominant staining of DMT1 at the
apical membrane.20
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Hephaestin |
Sex-linked anemia (sla) is a disorder that highlights the
selectivity of the enterocyte basolateral iron transport machinery and
emphasizes its role in the regulation of iron absorption. Sla mice
suffer the paradox of iron-overloaded enterocytes and insufficient
amounts of plasma iron for the production of red blood cells. Although
dietary iron absorption by the enterocyte is relatively normal, efflux
of iron through the basolateral membrane and into the plasma is
inhibited.103,104 The iron that remains trapped within the
sla enterocyte is hypothesized to be lost with exfoliation of these
cells.30 Postnatal anemia is corrected as the mouse
matures, but body iron stores remain depleted throughout the lifetime
of the mouse, suggesting the total iron demand is never
met.105,106
The sequence for hephaestin, the protein product of the gene mutated in
the sla mouse,5 has significant homology to the serum
protein, ceruloplasmin.107,108 Ceruloplasmin is a serum multicopper ferroxidase required for efficient recycling of iron between storage and donation sites in the liver, reticuloendothelial system, and the blood.109-111 The cloning of hephaestin
emphasizes the role of copper in the transfer of iron from the
enterocyte to the plasma. Copper is required for efficient iron
transport in biologic systems from yeast to mammals and may even be
considered to have a regulatory role because of the selectivity of iron
transporters for ferrous or ferric iron forms.112 The 194 amino acid deletion in hephaestin that is responsible for the sla
phenotype is expected to prevent oxidation of iron and transport across
the basolateral membrane of the enterocyte.5 Whether the
proposed oxidase activity of the hephaestin is necessary for the
selectivity of a specific basolateral iron transporter, the selectivity
of another iron transport protein, or to maintain a concentration
gradient of ferrous iron across the basolateral membrane is not known.
Unlike ceruloplasmin, the C-terminal portion of the hephaestin sequence
has a predicted membrane-spanning domain that would orient the
multicopper ferroxidase activity on the cell surface or in the lumen of
vesicles to act in concert with an iron exporter. In situ hybridization
has localized hephaestin to the enterocytes of the villus, excluding
the crypt cells,5 which confirms its role in the transport
of iron through these cells (Figure 2). Immunostaining has localized
hephaestin to perinuclear compartments,113 indicating that
it may be part of a biosynthetic compartment like the trans-Golgi, or
that it cycles, like transferrin receptor, between the basolateral
membrane and endocytic compartments. The vesicular localization of
hephaestin raises the possibility that iron derived from the cytoplasm
could be loaded onto a specific carrier such as
apotransferrin.114,115 Alternatively, the vesicular localization may prevent interaction of the iron targeted for export
with undesired intracellular iron targets. 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. Future experiments that coexpress Ferroportin1/Ireg1/MTP1 and hephaestin in tissue culture or
Xenopus expression systems may identify complementary roles
for these proteins.
The mutated gene products in both sla and hereditary hemochromatosis
have been shown recently to modulate the same iron absorption pathway.
HFE knockout mice bred to sla mice have higher hepatic iron levels than
wild-type mice, but much lower than HFE knockout mice.89
Although these experiments suggest that the additional iron transported
in hereditary hemochromatosis utilizes the hephaestin pathway, HFE and
hephaestin are not expected to physically interact. HFE is localized to
epithelial cells located in the duodenal crypts, whereas hephaestin is
localized to epithelial cells located on the duodenal villus. How HFE
might modulate hephaestin is not known, but the iron set point
established by HFE in the cells of the crypt may determine the activity
of hephaestin in the enterocyte.
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Model for iron homeostasis |
On the basis of these recent developments in the identification of
iron transport machinery, we propose a speculative, but testable, model
for the maintenance of iron homeostasis (Figure 3). Intestinal regulation of iron
homeostasis begins in the crypt where the regulatory set point for iron
uptake is established. Temporal and spatial separation of regulatory
machinery is required for the appropriate regulation of what will be
the final level of iron transport across the mature enterocyte. Because
the HFE- and transferrin receptor-expressing cells of the intestinal
crypt are not fully differentiated116,117 and do not
express the DMT1 protein,6,20 they are not sensitive to
iron levels in the lumen of the intestine. However, the body stores
regulator and possibly the erythropoietic regulator can communicate the
status of iron repletion and erythropoiesis through the plasma to these undifferentiated cells. By establishing the absorptive set point of the
enterocyte in the undifferentiated state, the duodenum can isolate the
signals received from the plasma without the confounding influence of
the dietary iron pool derived from the lumen of the intestine, or the
iron pool in transit across the epithelial layer.
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| Figure 3.
Hereditary hemochromatosis exemplifies inappropriate
regulation of the iron absorptive setpoint in the crypt.
Individuals with hereditary hemochromatosis (HH) have decreased levels
of functional HFE. This contributes to a higher labile iron pool in the
precursor cells of an individual with hereditary hemochromatosis than
an individual with functional HFE (wild type). When the precursor cell
of a hereditary hemochromatotic individual differentiates, the labile
iron pool will initially be high. We speculate that this increase in
the labile iron pool up-regulates machinery responsible for basolateral
iron transfer such as Ferroportin1/Ireg1/MTP1 (F/I/M). The increased
amount of basolateral iron efflux will lead to a depletion of the
labile iron pool, which will increase levels of the apical iron
transporter, DMT1. If Ferroportin1/Ireg1/MTP1 is a very stable protein,
or its activity exceeds that of DMT1 in the individual with hereditary
hemochromatosis, the iron efflux activity of that enterocyte will
overcome the uptake activity of DMT1, keeping intracellular iron levels
low. This model explains why individuals with hereditary
hemochromatosis have higher levels of DMT1 and low ferritin levels in
their duodenum and can be tested further by determining the activity of
Ferroportin1/Ireg1/MTP1 in hereditary hemochromatotic individuals and
controls as well as in HFE-deficient mice.
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HFE reduces the amount of iron absorbed from
transferrin,84-86,92,93 stepping down the
concentration of the labile iron pool (Figure 3). The set point
established by the labile iron pool will determine the IRP RNA binding
activity,58 iron-regulated transcriptional
activity,67,68 and the modulation of iron-dependent posttranslational trafficking20,35 and degradation
events.69,70 Thus, even before differentiation to an
enterocyte, the set point for intestinal regulation of iron transport
is determined by the labile iron pool of its precursor. The regulatory
activities are set in place and will perform their respective functions
when proteins specific to the differentiated enterocyte are expressed.
Differentiation occurs in a gradient along the crypt/villus axis,
turning off the expression of proteins specific to the crypt and
inducing the expression of enterocyte-specific
proteins.1,3,4 With the initial synthesis of
enterocyte-specific proteins, the set point of the labile iron pool
that was established in the crypt determines the relative amounts of
those proteins that are iron regulated. After differentiation induces
expression of the iron transport machinery, changes in the labile iron
pool are likely to occur. Whether iron-dependent regulation of these
proteins will affect transport through the enterocyte will depend on
the stability of the individual proteins. Iron-dependent
transcriptional and translational regulation will not affect the
activity of proteins with long half-lives, whereas iron-dependent
degradation will.
The identification of IREs on the mRNA of DMT1 and
Ferroportin1/Ireg1/MTP111,19,34,35 suggest they are iron
regulated through IRPs and the labile iron pool. Regulation of these 2 proteins will establish the transport capacity of the fully
differentiated enterocyte. Their balance is best exemplified by the
hereditary hemochromatosis defect (Figure 3). In the enterocyte
precursors of individuals with hereditary hemochromatosis, the
concentration of the labile iron pool is increased compared with
individuals with functional HFE. On differentiation of the hereditary
hemochromatotic enterocyte, the increased labile iron pool increases
the amount of Ferroportin1/Ireg1/MTP1 and the capacity for iron
transport into the plasma, consistent with the hereditary
hemochromatosis defect observed by McLaren and
colleagues.72 At the same time, this increased regulatory
iron pool reduces DMT1 protein levels.
The enterocytes of individuals with hereditary hemochromatosis have low
ferritin levels91 and increased DMT1 message
levels15,19 in the face of saturated body iron stores.
Although the latter finding may seem to conflict with our model for
regulation, we speculate that the levels of DMT1 and ferritin in the
enterocytes of hereditary hemochromatotic individuals reflect the
final, iron-depleted, steady state achieved by the increased activity
of Ferroportin1/Ireg1/MTP1. If Ferroportin1/Ireg1/MTP1 transport
surpasses that of DMT1 in individuals with hereditary hemochromatosis,
intracellular iron stores from ferritin and the labile iron pool will
be depleted, activating IRP RNA binding activity. The increased IRP RNA
binding activity may lead to an increase in DMT1 protein, or the
decrease in the labile iron pool may alter protein trafficking events
and redistribute DMT1 to the apical membrane. Similar regulation
leading to increased Ferroportin1/Ireg1/MTP1 protein activity in
macrophages may explain why the Kupffer cells of hereditary
hemochromatotic individuals are relatively free from iron
deposits118,119 and have increased IRP RNA binding
activity,95 whereas the rest of the liver is iron loaded.
Experiments that quantitate relative DMT1 and Ferroportin1/Ireg1/MTP1
levels and activity in control and hereditary hemochromatosis samples
and in HFE-deficient mouse models will reveal the suitability of this model.
Enterocytes may continue to be influenced after differentiation is
complete by external signals such as the erythropoietic or hypoxic
regulator that has been shown to up-regulate mucosal iron transfer in
the hypotransferrinemic mouse.49,102 Up-regulation of
Ferroportin1/Ireg1/MTP1 has been observed in the hypotransferrinemic mouse34 and may be the direct result of changes in
transcriptional activity induced by either regulator. Because the iron
loading of the hypotransferrinemic mouse is more severe than that of
the HFE knockout mouse, the regulation of Ferroportin1/Ireg1/MTP1 is
likely to differ between these 2 mouse models. A hierarchy of
regulation through transcriptional, translational and degradation events, as well as the regulation of accessory proteins like hephaestin is likely to fine-tune the enterocyte iron export machinery that has
been described. Experiments that test for differences in
Ferroportin1/Ireg1/MTP1 activity in hypotransferrinemic and
HFE-deficient mice may reveal differences in its regulation.
Finally, key to further understanding the details of iron homeostasis
in the intestine will be the identification of the erythroid and body
iron stores regulators and the mechanisms by which they regulate iron
transporters, and possibly other iron-related proteins such as HFE and hephaestin.
| |
Footnotes |
Submitted February 11, 2000; accepted July 28, 2000.
Supported by National Institutes of Health (NIH) grant DK 54488. C.N.R.
was supported in part by the Training Program in Molecular Hematology,
T32-HL00781, NIH National Heart, Lung, and Blood Institute.
The publication costs of this
article were defrayed in part by
page charge payment. Therefore,
and solely to indicate this fact,
this article is hereby marked
"advertisement"
in accordance with 18 U.S.C.
section 1734.
Reprints: Caroline A. Enns, Department of Cell and
Developmental Biology, L215, Oregon Health Sciences University,
Portland, OR 97201-3098; email: ennsca{at}ohsu.edu.
| |
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Abstract
Introduction