Biochimie 91 (2009) 1223–1228

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Biochimie
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Review

Hepcidin, the iron watcher

Lydie Viatte, Sophie Vaulont*
Institut Cochin, Département Endocrinologie, Métabolisme et Cancer, Paris F-75014 France; Inserm, U567; Université Paris Descartes, Faculté de Médecine René Descartes;
CNRS, UMR-S 8104

a r t i c l e i n f o a b s t r a c t

Article history: Hepcidin, a peptide hormone produced by the liver, constitutes the master regulator of iron homeostasis
Received 10 April 2009 in mammals allowing iron adaptation according to the body iron needs. In recent years there has been
Accepted 15 June 2009 important breakthrough in our knowledge of hepcidin regulation that has also implications for under-
Available online 23 June 2009
standing the physiopathology of human iron disorders. Different aspects of hepcidin regulation will be
considered in this review, including regulation by the iron status and the BMP6/HJV/SMAD pathway.
Keywords:
Hepcidin dysregulation in iron disorders will be also discussed. Although much can already be accom-
Metal
plished for treating iron disorders using the knowledge that has currently been developed, additional
Hepcidin
Iron disorders issues will be challenging for the coming years.
BMP/hemojuvelin Ó 2009 Published by Elsevier Masson SAS.
HFE/TfR

1. Introduction 2. Discovery of hepcidin

Iron is a vital biocatalyst that coexists in an oxidised insoluble
(Fe3þ) or a reduced soluble form (Fe2þ). The chemical properties of
iron makes it an essential element for many functions in particular
transport of oxygen. In mammals, 1–2 mg of iron are absorbed daily
by the duodenum, this represents the amount lost daily through
normal blood loss and desquamation. The main consumer of iron in
the body is the bone marrow for the production of erythrocytes
(approximately 20 mg iron/day). This iron is recycled by the
macrophages of the reticulo-endothelial system that phagocytose
senescent red blood cells, degrade hemoglobin containing iron and
release iron in the bloodstream [1].
The dark side of the metal is that, in excess, it can be toxic and
produce free radicals through the Fenton reaction. Human iron
disorders unfortunately illustrate these two aspects of iron:
patients with iron deficiency due to poor iron content in the diet,
abnormal blood loss, or chronic disease, but also, in rare cases, with
inherited diseases, present with anemia. On the other side of the
spectrum, patients suffering from iron overload, mainly hereditary
hemochromatosis (HH), have multiple symptoms due to organs
dysfunction such as diabetes, arthritis, liver fibrosis, cirrhosis,
cardiomyopathy and hypogonadism. Iron homeostasis must
therefore be finely tuned. First discovered as an antimicrobial
peptide, hepcidin proved to be the long-sought iron hormone.
* Corresponding author. Institut Cochin, Faculté de Médecine Cochin Port Royal,
24, rue du Faubourg Saint Jacques 75014 Paris, France. Tel.: þ33 1 44412408; fax:
þ33 1 44412421.
E-mail address: sophie.vaulont@inserm.fr (S. Vaulont).
Although dysregulations of iron metabolism were first
described in the XIXth century, little was known until recently
about the molecules involved in the regulation of iron homeostasis.
In 2001, two independent laboratories purified a new antimicrobial
peptide from blood [2] and urine [3]. This small 25 amino acid
peptide produced by the liver proved to be the iron hormone
sought for many years. It was baptised hepcidin, ‘‘hep’’ for hepatic
and ‘‘cidin’’ for its antimicrobial activity. As expected for an iron-
regulatory hormone, hepcidin was found to be up-regulated by iron
overload [4] and downregulated by iron deficiency [5]. Studies in
transgenic mice showed that hepcidin deficiency leads to iron
overload [6] and that overexpression of hepcidin leads to severe
iron deficiency and anemia [7]. Thus, hepcidin maintains iron
homeostasis by inhibiting the intestinal absorption and the release
of iron by macrophages. This hyposideremic activity of hepcidin is
mediated through the control of the surface expression of the iron
exporter ferroportin on duodenal enterocytes and iron recycling
macrophages. Hepcidin was shown to be able to bind to ferroportin,
leading to the internalization and degradion of the iron exporter
[8], thereby decreasing iron availability in the circulation.
3. Regulation of hepcidin
Hepcidin is mainly produced by the liver but recent studies
describe production of hepcidin in other tissues: macrophages
[9–11], pancreatic beta cells [12], kidney [13], and adipocytes [14].
However, the contribution of extrahepatic hepcidin to the circulating
pool is unknown and, in contrast to liver hepcidin, hepcidin gene

0300-9084/$ – see front matter Ó 2009 Published by Elsevier Masson SAS.

doi:10.1016/j.biochi.2009.06.012
1224 L. Viatte, S. Vaulont / Biochimie 91 (2009) 1223–1228
expression in these cell types seems to be more sensitive to inflam-
mation than to iron [10,11,14]. A possible role of extrahepatic hepci-
din could be the control of local iron fluxes under particular stimuli.
Hepcidin is produced as a pre-pro-protein of 84 amino-acids
composed of a signal peptide, a pro-region and the mature 25
amino acid peptide. Pro-hepcidin was shown to be biologically
inactive [15]. In the hepatocyte, hepcidin maturation occurs via
a furin cleavage site recognized mainly by the prohormone con-
vertase furin [16–18]. The exact conditions and mechanisms of
regulation of hepcidin maturation and secretion are largely
unknown, and the role for the presence of pro-hepcidin in the
serum remains elusive. Only one commercially available ELISA is
used to detect serum pro-hepcidin. However, the antibody is
detecting a non-matured form of 10 kDa [19] which would corre-
spond to the pre-pro-hepcidin containing the peptide signal rather
than pro-hepcidin estimated at 7.8 kDa. Furthermore, to date, the
physiological significance of this assay, and thus its interest in
clinical studies, is not validated and no relatioship between pro-
hepcidin and iron absorption was demonstrated (for review [20]).
3.1. Regulation by iron status
To limit iron toxicity, hepcidin is physiologically induced in
situation of iron overload to decrease circulating iron levels [4,21].
Conversely, during iron deficiency, hypoxia or erythroid expansion
[5,22–24], hepcidin expression is reduced to allow efficient iron
mobilization.
Identification of the proteins involved in HH, namely HFE, TfR2
and HJV, shed a new light in understanding, at the molecular level,
the iron regulation of hepcidin. Mutations in these proteins lead to
increased iron absorption and recycling due to inappropriate levels
of hepcidin [25].
3.1.1. HFE and transferrin receptors (TfR1 & TfR2)
HFE is the main gene responsible for HH. It is a member of HLA
class I family. HFE is expressed in many different tissues, including
enterocytes and hepatocytes. With the increased iron absorption in
hemochromatotic patients and evidence that HFE could interact
with transferrin receptor 1 (TfR1) [26], HFE was first thought to act
as a regulator of iron homeostasis by sensing iron at the baso-lateral
surface of immature enterocytes, also referred to as the ‘‘crypt
model’’ [27]. Recently, with the discovery of hepcidin, attention was
brought to the liver as the center for iron regulation. Tissue-specific
HFE knockout mouse models demonstrated that, while ablation of
HFE in enterocytes had no effect on iron metabolism [28], liver-
specific knockout of HFE recapitulated the phenotype of total HFE
KO [29], i.e. multivisceral iron overload.
While the exact mechanisms by which HFE regulates hepcidin
expression in the liver are not completely known, recent data help
to uncover possible pathways. First, it was shown that HFE can also
interact with TfR2 [30] in addition to TfR1. While TfR1 is ubiquitous
and used by most of the cells for uptake of iron bound to transferrin
(Tf-Fe2), TfR2 expression is more restricted, with high levels found
in the liver [31], its affinity toward Tf-Fe2 is much weaker and, in
contrast to TfR1, TfR2 levels respond to Tf-Fe2 independent of
changes in cellular iron status [32,33]. TfR2 was found to be
mutated in patients suffering from HH [34] demonstrating that it is
not essential for iron uptake by the hepatocytes. TfR2 is thought to
act with HFE to regulate hepcidin expression. A recent model is
proposing that when Tf-Fe2 is present in high amounts, it binds to
TfR1, releasing HFE that can then bind to TfR2 [35,36]. Conse-
quently, the HFE-TfR2 complex would signal, possibly through
the MAPK/ERK pathway [37], to induce hepcidin expression
(see Figure). It remains unclear whether HFE is necessary for
iron-sensing or just for basal expression of hepcidin [38].
3.1.2. HJV, BMP and TMPRSS6
Hemojuvelin (HJV or RGMc) was identified in patients pre-
senting a severe form of HH: hemochromatosis type 2 or juvenile
hemochromatosis [39]. HJV is a Bone Morphogenetic Protein (BMP)
co-receptor [40]. BMPs are members of the TGFb family; they
induce hepcidin gene transcription through the SMAD1,5,8/SMAD4
pathway [41](see Fig. 1). Ablation of SMAD4 specifically in the liver,
triggers an iron overload in multiple organs due to decreased levels
of liver hepcidin [42]. Several different BMPs were able in vitro
[40,42,43] and in vivo [41] to induce hepcidin but recent data
suggest that BMP6 is essential for hepcidin up-regulation by iron.
BMP6 gene expression is directly regulated by the amount of iron
and increasing amount of phosphorylation of Smad1,5,8 could be
directly related to iron-dependent expression of hepcidin in vivo
[44,45]. Furthermore, recent reports demonstrate that BMP6
knockout mice present the same iron overload phenotype as
SMAD4 and HJV KO mice due to hepcidin deficiency [46,47]
demonstrating that other BMPs cannot compensate for the loss of
BMP6. Two functional BMP response elements (RE) have been
described in hepcidin promoter: one located at position 84
nucleotides from transcription start, and one distal element located
at position 2301 [48,49]. Very recently a patient with a mutation
in the proximal BMP-RE was described [50]. This patient has low
serum hepcidin level and massive iron overload associated with
hypogonadism, melanodermia and osteoporosis, highlighting the
critical role of BMP/HJV pathway to regulate hepcidin expression.
HJV is a GPI-anchored protein that can be cleaved and released
in a soluble form, sHJV[51]. Interestingly, as for hepcidin matura-
tion, sHJV is produced after cleavage by the prohormone convertase
furin [52]. Release of sHJV is regulated by iron [51,53] and hypoxia
[54]. In contrast to membrane-bound HJV, sHJV inhibits iron-
induced hepcidin production and when injected into mice,
increases serum iron through reduction of phosphorylated
SMAD1,5,8 levels [41]. A possible mechanism for sHJV inhibition of
hepcidin is that it competes with HJV for binding with BMPs
(see Fig. 1).
A new partner of the HJV/BMP pathway was recently involved in
hepcidin regulation: the serine protease TMPRSS6 (also known as
matriptase-2, for review, see [55]). This transmembrane serine
protease is mainly expressed in the liver. Mice with ‘‘mask’’ muta-
tion of Tmprss6 are characterized by abnormal hair distribution and
iron-deficiency anemia associated with inappropriately high levels
of hepcidin [56]. Tmprss6 KO mice present a similar phenotype [57].
In humans, TMPRSS6 deficiency is responsible for iron-refractory
iron-deficient anemia (IRIDA) [58–60]. Anemia of these patients is
poorly improved by oral iron therapy due to inhibited iron
absorption. The high levels of hepcidin in spite of iron-deficiency
anemia suggest that TMPRSS6 is an inhibitor of hepcidin synthesis
[56]. In vitro data suggest that TMPRSS6 has proteolytic activity
against membrane-bound HJV [61] (see Fig. 1). How TMPRSS6 is
regulated by iron remains to be determined.
3.2. Regulation by inflammation
Linked to its function as an antimicrobial peptide, hepcidin is
also induced by inflammation. The induction of hepcidin in
inflammatory context is thought to play a major role in the setting
of anemia of inflammation (also called anemia of chronic diseases).
When mice are treated with turpentine oil or LPS, liver hepcidin
[4,22] but also macrophage hepcidin [62] is induced. In humans,
LPS was also shown to increase urinary hepcidin [63]. While IL6
[21,64,65] and IL1 b [65,66] induce hepcidin transcription, TNFa
seems to have no effect [9,64,67] or even repress hepcidin [21,66].
IL6-induced expression of hepcidin is dependent on the JAK/STAT3
pathway, and the STAT3 binding site has been identified in hepcidin
 L. Viatte, S. Vaulont / Biochimie 91 (2009) 1223–1228 1225

Fig. 1. The expression of hepcidin is dependent on opposing signalling pathways: the combined effects of the various pathways will determine hepcidin levels. In conditions of iron
deficiency, sHJV inhibitor is high, BMP6 activator is low and mHJV is degraded by the activated serine protease TMPRSS6, contributing to decreased hepcidin gene expression.
The activity of an unknown factor mediated by increased erythropoiesis has also been postulated to contribute to hepcidin decrease to allow iron mobilization. Similarly, by
a yet unknown mechanism, has GDF15 been proposed as a direct repressor of hepcidin in cultured cells. EPO was proposed to act either directly (through EPOR-mediating decreased
C/EBPa activity) or indirectly, by inhibiting both inflammatory and iron-sensing pathway by decreasing STAT3 and SMAD signaling. Finally, stabilization of HIFa by iron deficiency or
hypoxia was shown to downregulate hepcidin expression. As a consequence of iron deficiency, TfR1 is bound to HFE. In conditions of increased holotransferrin, BMP6 is increased,
sHJV is decreased and the HJV/SMAD pathway is fully activated leading to enhanced hepcidin gene expression. As serum iron saturation increases, HFE is dislodged from its
overlapping binding site on TfR1 by holotransferrin. HFE is then freed to interact with TfR2 and to signal, possibly through the activation of ERK1/2, for the up-regulation of hepcidin.
In inflammatory conditions, the classical IL6/JAK/STAT3 pathway has been characterized to be responsible for hepcidin gene activation (the crosstalk between the inflammatory
signals and the iron-sensing pathway is not represented).

promoter next to the proximal BMP-RE [68–70] (see Fig. 1). It seems
that there is some crosstalk between the BMP/SMAD and JAK/STAT
pathways to control hepcidin levels: mutation of the proximal
BMP-RE decreases IL6 response [70] as well as sHJV treatment [41].
In contrast, BMP2 response is increased when STAT3 binding site is
deleted [70] and conversely hepcidin response to LPS is increased in
BMP6 KO mice [46].
3.3. Regulation by anemia, hypoxia and increased erythropoiesis
Iron-deficient anemia and hypoxia inhibit the synthesis of
hepcidin allowing iron supply to match erythropoietic demand
[22]. This response is most likely multifactorial and some of the
signals require active erythropoiesis [71] (see Fig. 1).
Recently, Tanno et al.[72] reported that GDF15, a member of the
TGF-b family, mediates hepcidin repression in thalassemia. Thal-
assemia patients present anemia due to hemolysis of abnormal red
blood cells and subsequent expansion of the erythroid compart-
ment. These patients have high concentrations of GDF15 in their
serum and Tanno et al. further showed that GDF15 could repress
hepcidin expression directly on hepatoma cells. Interestingly,
GDF15 was recently shown to be up-regulated by stimuli that
deplete cells of iron [73]. In agreement, induction of serum GDF15
was observed in iron-deficient subjects as well as following iron
chelator administration in normal subjects [73].
Erythropoietin (EPO) is synthesized by the kidney in hypoxic
conditions and acts as an anti-apoptotic agent on erythroblasts
through its receptor EPOR. As observed in mice under hypoxia [22],
injection of EPO inhibits hepcidin expression [23]. Pinto el al.
recently proposed that EPO could act directly to repress hepcidin in
hepatocytes through EPOR-mediated regulation of the transcrip-
tion factor C/EBPa [74]. Alternatively, Huang et al. recently
proposed that EPO can inhibit hepcidin expression indirectly via
the suppression of STAT3 and SMAD4 signaling in vivo [75].
The major hypoxia-mediated gene regulation system, involving
Hypoxia Inducible Factors, HIFa was recently reported to control
hepcidin synthesis [76]. In normoxia, the regulatory subunit a is
hydroxylated by the oxygen- and iron-dependent prolyl-hydroxy-
lases (PHD), and degraded through the ubiquitin-proteasome
pathway via its interaction with the von Hippel-Lindau (VHL)
tumor suppressor protein. Conversely, under hypoxia or iron
depletion, hydroxylation is inhibited resulting in stabilization of the
a-subunit, heterodimerization with ARNT, nuclear translocation
and trans-activation of HIF-target genes such as EPO [77]. Hepcidin
was recently shown to be a direct negative target of HIF-1: HIF-1
binds to the hepcidin promoter, decreasing hepcidin levels.
Consequently, in mice harboring hepatic deletion of vHL, HIF 1 is
stabilized and mice presented with dramatic decreased hepcidin
levels [76] (see Fig. 1).
Finally, an increase in reactive oxygen species (ROS) levels in
hypoxic conditions has also been proposed as a possible mecha-
nism responsible for hepcidin repression via alteration of C/EBPa
and STAT-3 activities [78].
4. Mode of action of hepcidin
Hepcidin was identified for its antimicrobial properties and
classified as member of the defensin family [2,3]. The role of
1226 L. Viatte, S. Vaulont / Biochimie 91 (2009) 1223–1228
hepcidin as an antimicrobial peptide in mammals has been regar-
ded as unlikely since this antimicrobial activity was efficient at
concentrations much higher than those found in the blood [2,3] and
by the fact that physiological blood concentrations of NaCl was
shown to inhibit this activity [3]. Furthermore, exogenous hepcidin
added to infected macrophages enhanced bacterial growth in the
macrophages [79]. This effect is thought to be mediated by iron
retention caused by decreased ferroportin levels of the macro-
phages, the intracellular pathogens using this iron for their
proliferation.
While circulating hepcidin seems to be inefficient as an anti-
microbial peptide, it was recently proposed that hepcidin produced
endogenously by the macrophages and localized in the phagosome
could play a role in host defense against tuberculosis by causing
structural damage to the mycobacteria [11]. Of note, while hepcidin
peptide of 20 amino-acids purified from the urine have similar
antimicrobial activity as the 25 amino acid peptide [3], it it is unable
to degrade ferroportin in vitro and in vivo [80], showing that these
two functions of hepcidin are not overlapping.
The role of hepcidin as a regulator of homeostasis has been
extensively studied and a mechanism for ferroportin degradation
has been proposed. It was first shown that overexpressed tagged-
ferroportin could be internalized and degraded in vitro by hepcidin
treatment [8]. This observation could be reproduced by other
groups in vitro [81,82] and in the more physiological conditions of
bone-marrow derived macrophages [83]. In vivo, hepcidin defi-
ciency was shown to be associated with increased ferroportin
protein levels [84]. The mechanism by which hepcidin binding to
ferroportin leads to degradation of the iron exporter was suggested
by the work of De Domenico et al. They showed that hepcidin
binding to its binding site (HBD for Hepcidin Binding Site) on the
exporter [85] leads to JAK2-dependent tyrosines phosphorylation
[86,87]. Once internalized, ferroportin is dephosphorylated and
degraded after ubiquitination [86]. Whether ferroportin is
a monomer or a multimer is still a point of controversy [88].
Recently ferroportin was proposed to be a dimer and it was shown
that both monomers have to bind hepcidin for JAK2 to bind to and
to phosphorylate ferroportin [87]. These results, showing that
cooperation between the ferroportin monomers is required for
hepcidin-mediated ferroportin down-regulation, provide a molec-
ular explanation for the dominant inheritance of hepcidin-resistant
iron overload disease (see below).
5. Hepcidin at the center of iron disorders
5.1. Hereditary hemochromatosis (HH)
Hemochromatosis was first described and named in the XIXth
century. But it’s only in 1996 that mutations in HFE were identified
as responsible for genetic hemochromatosis [89]. C282Y mutation
of HFE is very frequent and when at homozygous state, is respon-
sible for the most common form of hemochromatosis. Later, iden-
tification of mutations in TFR2, HJV, hepcidin and ferroportin genes
followed(for review, see [90]). Hemochromatosis is characterized
by iron overload of multiple organs causing cirrhosis, cardiomy-
opathy, arthritis, diabetes when not treated. In the most severe
forms, due to mutations in HJV or hepcidin genes, patients present
severe cardiac disease and hypogonadism.
All forms of HH are supposed to result from either inappropriate
levels of hepcidin [39,91–95] or, for mutations in ferroportin gene,
from resistance to hepcidin. It is now assumed that the severity of
symptoms is associated to the remaining hepcidin levels found in
the patients. This hypothesis is reinforced by the fact that muta-
tions in hepcidin genes in the context of patients homozygotes
for C282Y aggravates the phenotype of the patients [96–98].
Furthermore, studies in mice have shown that overexpression of
hepcidin can prevent [99] or cure [100] iron overload of Hfe KO
mice.
The iron exporter ferroportin itself was found to be mutated in
the iron overload disorder called the ferroportin disease (for
review, [101]). Ferroportin disease has an autosomal dominant
mode of inheritance and phenotypic characteristics that differen-
tiate it from the other forms of HH.
Interestingly, it was shown that specific mutations are respon-
sible for the two main phenotypes of the ferroportin disease.
Mutations that result in loss or reduction in iron transport activity
lead to the typical macrophage iron loading with high serum
ferritin and normal transferrin saturation. Other mutations retain
normal iron transport activity but are insensitive to hepcidin-
induced internalization leading thus to an elevated transferrin
saturation, moderately increased serum ferritin and hepatocyte
iron accumulation as seen in classical HH.
5.2. Anemia of inflammation (or anemia of chronic diseases)
Low-grade inflammation is usually associated with anemia.
While proinflammatory cytokines can directly inhibit erythropoi-
esis, EPO synthesis or downregulate ferroportin, interests slowly
grew on the contribution of hepcidin in the setting of anemia of
inflammation (for review, see [102]). In mice, decreased serum iron
consequently to an acute inflammation caused by turpentine
injection was prevented in hepcidin-deficient mice [22]. In
humans, although up-regulation of hepcidin was found in patients
with anemia of chronic diseases [24,64,103], further investigations
are needed to determine the precise role of increased hepcidin
levels in the physiopathogeny of anemia of inflammation.
5.3. Detection of hepcidin
The discovery of the hormonal iron-regulating role of hepcidin,
followed by the elucidation of its mechanism of action -to regulate
ferroportin levels- herald exciting times in the field of iron
metabolism and related disorders and offer new clinical potential in
terms of diagnosis and therapeutics. It became rapidly obvious that
a reliable method to detect mature hepcidin in human samples was
highly desirable for the diagnosis and clinical management of iron
disorders. However, the generation of hepcidin antibodies has been
hampered due to the very low immunogenicity of the peptide. To
date, only one team has produced antibodies against the biologi-
cally active peptide. They first developed a dot blot system for
urinary hepcidin measurement [21], and recently succeeded in
elaborating an ELISA detecting serum hepcidin [103]. To bypass the
difficulty of measuring serum hepcidin levels, some laboratories
have developed semi-quantitative methods using mass spectrom-
etry [104–107] (for review, see [108]). However, these methods
have reported limits of detection and reproducibility. Interestingly,
De Domenico et al. used an innovating assay to measure hepcidin in
the serum. Using the synthetic peptide corresponding to the HBD of
ferroportin, they developed a competitive assay with radiolabeled
hepcidin to measure hepcidin levels in biological fluids [85].
6. Conclusion
The discovery of hepcidin has revolutionized the field of iron
homeostasis. This small antimicrobial peptide proved to be the
long-sought iron hormone and the liver became the center of
interest, especially to understand the many complexes pathways
regulating hepcidin expression (see Fig. 1). Its role in hemochro-
matosis helped to sort out a heterogenous family of diseases into
one common etiology: dysregulation of hepcidin.
 L. Viatte, S. Vaulont / Biochimie 91 (2009) 1223–1228 1227

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