| ironjustice@aol.com 2006-06-17, 4:25 pm |
| http://www.medscape.com/viewarticle/532533
Hepcidin Acts Against Iron Overload in Mice
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By David Douglas
NEW YORK (Reuters Health) May 17 - The iron regulatory peptide hepcidin
has beneficial effects on the pattern of cellular iron accumulation in
a mouse model of hematochromatosis, according to French and US
researchers.
"We previously demonstrated that hepcidin was able to prevent the iron
overload in a mouse model of hemochromatosis and we now provide
evidence that hepcidin could also be beneficial when the iron overload
is already established," senior investigator Dr. Sophie Vaulont told
Reuters Health.
In the April 1st issue of Blood, Dr. Vaulont of Institut Cochin, Paris
and colleagues note that it appears that hepcidin is a key regulator of
iron homeostasis that acts by limiting both intestinal iron absorption
and macrophage iron release.
In mutant mice that had already developed iron overload, the
researchers employed chronic hepcidin induction by means of doxycycline
delivered via their drinking water.
The result was a change in cellular iron accumulation that led to
increased iron in tissue macrophages and duodenal cells but less iron
in hepatocytes. These changes were associated with decreased expression
of the iron exporter ferroportin.
The findings, added Dr. Vaulont, are "of particular importance not only
for hereditary hemochromatosis but also for secondary iron overload."
In an accompanying editorial, Dr. Clara Camaschella of Universita
Vita-Salute San Raffaele, Milan, notes that hepcidin treatment shows
promise, but how to achieve "a balance between hepatocyte iron
reduction and development of anemia will be crucial."
Blood 2006;107:2952-2958.
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http://www.bloodjournal.org/cgi/content/full/107/7/2952
Blood, 1 April 2006, Vol. 107, No. 7, pp. 2952-2958.
Prepublished online as a Blood First Edition Paper on December 8, 2005;
DOI 10.1182/blood-2005-10-4071.
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RED CELLS
Chronic hepcidin induction causes hyposideremia and alters the pattern
of cellular iron accumulation in hemochromatotic mice
Lydie Viatte, Ga=EBl Nicolas, Dan-Qing Lou, Myriam Bennoun,
Jeanne-Claire Lesbordes-Brion, Fran=E7ois Canonne-Hergaux, Kai Sch=F6nig,
Hermann Bujard, Axel Kahn, Nancy C. Andrews, and Sophie Vaulont
>From the Institut Cochin, D=E9partement de G=E9n=E9tique, D=E9veloppement
et Pathologie Mol=E9culaire, Paris; Institut National de la Sant=E9 et de
la Recherche M=E9dicale (INSERM) U567, Centre National de Recherche
Scientifique (CNRS) Unit=E9 mixte de Recherche (UMR) 8104, Universit=E9
Paris Descartes, Facult=E9 de M=E9decine Ren=E9 Descartes, UMR-S 8104,
Paris; Institut National de la Transfusion Sanguine, Inserm U665,
Paris; Inserm U409, Facult=E9 deM=E9decine Xavier Bichat, Paris, France;
Zentrum f=FCr Molekul=E4re Biologie, Heidelberg, Germany; and Children's
Hospital Boston, Dana-Farber Cancer Institute, Harvard Medical School,
Howard Hughes Medical Institute, Boston, MA.
Abstract
Top
Abstract
Introduction
Materials and methods
Results
Discussion
References
We report the generation of a tetracycline-regulated (Tet ON)
transgenic mouse model for acute and chronic expression of the iron
regulatory peptide hepcidin in the liver. We demonstrate that
short-term and long-term tetracycline-dependent activation of hepcidin
in adult mice leads to hypoferremia and iron-limited erythropoiesis,
respectively. This clearly establishes the key role of hepcidin in
regulating the extracellular iron concentration. We previously
demonstrated that, when expressed early in fetal development,
constitutive transgenic hepcidin expression prevented iron accumulation
in an Hfe-/- mouse model of hemochromatosis. We now explore the effect
of chronic hepcidin expression in adult Hfe-/- mice that have already
developed liver iron overload. We demonstrate that induction of chronic
hepcidin expression in 2-month-old Hfe-/- mice alters their pattern of
cellular iron accumulation, leading to increased iron in tissue
macrophages and duodenal cells but less iron in hepatocytes. These
hepcidin-induced changes in the pattern of cellular iron accumulation
are associated with decreased expression of the iron exporter
ferroportin in macrophages but no detectable alteration of ferroportin
expression in the hepatocytes. We speculate that this change in iron
homeostasis could offer a therapeutic advantage by protecting against
damage to parenchymal cells.
Introduction
Top
Abstract
Introduction
Materials and methods
Results
Discussion
References
Although iron is essential for many cellular processes, particularly
for mammalian erythropoiesis, iron in excess can be deleterious as it
triggers production of free radicals. To maintain iron homeostasis,
there is tight regulation of iron absorption by the duodenum and iron
recycling from senescent erythrocytes by tissue macrophages. The
recently identified hepatic peptide hepcidin has been proposed to be
central to this regulation, acting as the principal iron-regulatory
hormone to maintain iron homeostasis. Hepcidin is a 25-amino acid
peptide synthesized by the liver, secreted into the bloodstream, and
excreted by the kidney.1,2 Hepcidin expression is increased in iron
overload3 and decreased in iron deficiency.4,5 Hepcidin-deficient mice
accumulate iron in parenchymal cells with sparing of the
reticuloendothelial system6 and, conversely, transgenic mice
constitutively expressing hepcidin have markedly lower iron stores
resulting in severe anemia.7 In humans, the important physiologic role
of hepcidin was demonstrated by the identification of homozygous
mutations of the hepcidin gene in patients with juvenile
hemochromatosis,8 a severe iron overload disorder characterized by
increased intestinal iron absorption, increased serum iron, and
deposition of excess iron in parenchymal cells. Together, these
observations are all consistent with that idea that hepcidin is a key
regulator of iron homeostasis that acts by limiting both intestinal
iron absorption and macrophage iron release. Recent studies indicate
that, to achieve this function, hepcidin binds to ferroportin,9 a
transmembrane iron transporter necessary for iron export out of
intestinal epithelial cells and macrophages.10 Hepcidin binding induces
internalization of ferroportin and its subsequent degradation.9
In humans, hepcidin dysregulation was demonstrated in 2 phenotypically
opposite iron disorders, hereditary hemochromatosis (HH) and the anemia
of inflammation (also referred to as the anemia of chronic disease).
Hepcidin production was reported to be deficient in patients with HH
attributable to mutations in HFE, TFR2, or HFE2,11-13 thus explaining
their persistently increased iron absorption in the face of iron
overload. In contrast, excessive hepcidin production was reported in
patients with inflammatory and infectious disorders associated with the
anemia of inflammation.14,15 Increased hepcidin expression is expected
to rapidly sequester iron in the macrophages and inhibit duodenal iron
absorption, 2 hallmarks of the anemia of inflammation.
Recently, transgenic and mutant mouse models with hepcidin deficiency
have provided significant insights into the important role of the
hepcidin-ferroportin axis in iron metabolism.16-19 In these models,
hepcidin deficiency correlated with up-regulated ferroportin protein in
enterocytes, leading to increased intestinal iron absorption and
increased plasma iron levels. In contrast, there have been few models
developed to study the effects of hepcidin overexpression. We
previously reported a transgenic mouse model in which the transthyretin
(TTR) promoter was used to drive constitutive hepcidin synthesis.20 Due
to the very early activity of the TTR promoter in the fetal liver, the
majority of the transgenic pups died within a few hours after birth
from systemic iron deficiency associated with severe microcytic,
hypochromic anemia. This phenotype suggested a hepcidin-dependent
blockade of placental iron transport resulting from transgenic fetal
hepcidin production late in gestation, when the endogenous hepcidin
gene is not detectably expressed. To circumvent the early effects of
hepcidin, we developed a conditional transgenic mouse model using a
tetracycline-dependent inducible system (Tet ON).21 This model allows
overexpression of hepcidin in the liver in response to doxycycline (a
tetracycline analog) treatment, allowing investigation of the effects
of hepcidin on iron absorption and recycling in adult animals. Here, we
report the effects of induced transgenic hepcidin expression on iron
homeostasis in normal mice and mice with genetic hemochromatosis
(Hfe-/- mice).
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