Transcript Indications for Successful Iron Overload Treatments and

Update on Hepcidin Regulation in
Different Disorders
Pierre Brissot, MD
Professor of Medicine
Liver Disease Department
University Hospital Pontchaillou
Rennes, France
Outline
Part 1: Hepcidin as the key hormone of iron
regulation
Part 2: Hepcidin in different human
disorders
• Iron disorders related to hepcidin deficiency
• Iron disorders related to hepcidin overproduction
• Other disorders associated with hepcidin imbalance
Hepcidin General Features
• “Hep” for hepatic and “cidin” for antimicrobial
activity1
• 25-amino-acid protein (derived from an
84-amino-acid precursor)2,3
• Coded by the HAMP gene (chromosome 19)3,4
• Mainly produced by hepatocytes4,5
1. Park CH, et al. J Biol Chem. 2001;276:7806-7810. 2. Piperno A, et al. World J Gastroenterol.
2009;15:538-551. 3. Lee PL, et al. Annu Rev Pathol. 2009;4:489-515. 4. Andrews NC. Blood.
2008;112:219-230. 5. Pigeon C, et al. J Biol Chem. 2001;276:7811-7819.
Body Iron Regulation by Hepcidin
Iron Deficiency
1
Body iron decrease
lowers hepcidin
synthesis in the liver
2
Hepcidin deficiency
targets the
duodenum and
spleen
3
Duodenal absorption of iron
increases
4
Splenic iron is released into
the circulation
5
Iron concentration in plasma
increases, leading to
restoration of iron balance
1
Hepcidin
2
Iron
5
3
Ganz T, et al. Am J Physiol Gastrointest Liver Physiol. 2006;290:G199-G203.
4
Hepcidin–Cellular Targets and
Mechanism of Action
1
Ferroportin
exports iron from
cell to plasma
2
Hepcidin circulates
in plasma
3
Hepcidin binds to
ferroportin on the
cell’s surface
4
Internalization
5
Ferroportin
degradation
6
Decreased ferroportin
exports less iron to
plasma
Cell
(enterocyte and
macrophage)
5
4
1
6
2
Brissot P, et al. Blood Rev. 2008;22:195-210.
3
Plasma
Ferroportin
HEPCIDIN
Regulation of Hepcidin Transcription1-3
Plasma
4
Tf
Sat
HJV
BMP6
TfR2
BMPR
1
HFE
TfR1
2
Membrane
5
MAPK/ERK
Cytosol
SMADs
3
Hepatocyte
Nucleus
1. Piperno A, et al. World J Gastroenterol. 2009;15:538-551. 2. Lee PL, et al. Annu Rev Pathol. 2009;4:489-515.
3. Calzolari A, et al. J Cell Sci. 2006;119:4486-4498. Graphic courtesy of Dr. P. Brissot.
Hepcidin-mRNA
Abbreviations: BMP, bone morphogenic
protein; BMPR, bone morphogenic
protein receptor; ERK, extracellular
signal regulated kinase; HJV,
haemojuvelin; MAPK, mitogen activated
protein kinase; TF sat, transferrin
saturation; TfR1, transferrin receptor 1;
TfR2, transferrin receptor 2.
Regulation of Hepcidin Transcription–Hypothetical1-3
1
Plasma
HJV
HJV
Tf
Sat
2
BMP
BMP6
TfR2
TfR2
BMPR
BMPR
HFE
TfR1
TfR1
Membrane
MAPK/ERK
SMADs
SMAD
Cytosol
Hepcidin-mRNA
Hepatocyte
Nucleus
1. Piperno A, et al. World J Gastroenterol. 2009;15:538-551. 2. Lee PL, et al. Annu Rev Pathol. 2009;4:489-515.
3. Calzolari A, et al. J Cell Sci. 2006;119:4486-4498. Graphic courtesy of Dr. P. Brissot.
Regulation of Hepcidin by Matriptase-2 Hypothetical
Plasma
2
1
Tf
Sat
HJV
HJV
BMP6
BMP
TfR2
TfR2
BMPR
BMPR
HFE
TfR1
TfR1
Matriptase-2
Membrane
SMADs
SMAD
Cytosol
Hepcidin-mRNA
–
Hepatocyte
Ramsay AJ, et al. Haematologica.
2009;94:840-849. Graphic courtesy of Dr. P. Brissot.
Nucleus
Outline
Part 1: Hepcidin as the key hormone of iron
regulation
Part 2: Hepcidin in different human disorders
• Iron disorders related to hepcidin deficiency
• Iron disorders related to hepcidin overproduction
• Other disorders associated with hepcidin imbalance
Types 1, 2, and 3 Haemochromatosis—
Quantitative Hepcidin Defect
1
HFE (type1)
or non-HFE
(type 2 or 3)
mutations
1
HFE or non-HFE
mutations decrease
hepcidin synthesis
in the liver
2
Hepcidin deficiency
targets the
duodenum and
spleen
3
Duodenal absorption of iron
increases
4
Splenic iron is released into
the circulation
5
Iron concentration in plasma
strongly increases
6
Increased plasma iron produces
parenchymal iron deposition
Brissot P, et al. Blood Rev. 2008;22:195-210.
Hepcidin
6
2
Iron
5
3
4
Quantitative Defect in HepcidinFerroportin Interaction—Types 1, 2, and 3
Haemochromatosis
1
Ferroportin
exports iron from
cell to plasma
2
Decreased
hepcidin circulates
in plasma
3
Decreased hepcidin
binds to ferroportin
on the cell’s surface
4
Internalization
5
Decreased
ferroportin
degradation
6
Increased ferroportin
exports more iron to
plasma
Cell
(enterocyte and
macrophage)
5
4
1
2
Brissot P, et al. Blood Rev. 2008;22:195-210.
3
6
Plasma
Type 4B Haemochromatosis—Qualitative
Hepcidin Defect
Hepcidin Resistance
1 Mutated
Cell
(enterocyte and
macrophage)
ferroportin
2 Normal hepcidin
level circulating in
plasma
3 Defect in hepcidin
binding to ferroportin
5
4
4 Decreased
ferroportin
degradation
1
5 Increased
ferroportin
6 Increased ferroportin
activity exports more
iron to plasma
2
Brissot P, et al. Blood Rev. 2008;22:195-210.
3
6
Plasma
Outline
Part 1: Hepcidin as the key hormone of iron
regulation
Part 2: Hepcidin in different human disorders
• Iron disorders related to hepcidin deficiency
• Iron disorders related to hepcidin overproduction1,2
• Other disorders associated with hepcidin imbalance
1. Finberg KE, et al. Nat Genet. 2008;40:569-571.
2. Theurl I, et al. Blood. 2009;113:5277-5286.
Anaemia of Inflammation/Chronic
Disease—Hepcidin Overproduction
1
Inflammation
1
Inflammation
increases hepcidin
synthesis in the liver
2
Hepcidin increase
targets the
duodenum and
spleen
3
Duodenal absorption of iron
decreases
4
Splenic iron released into
circulation is decreased
5
Overloaded macrophages
6
Plasma iron concentration
decreases, leading to anaemia
Brissot P, et al. Blood Rev. 2008;22:195-210.
Hepcidin
5
2
5
Iron
6
3
4
IL6 Mediation of Hepcidin in Inflammation
Inflammation
HJV
HJV
BMP
BMP6
TfR2
TfR2
BMPR
BMPR
TfR1
TfR1
MAPK/ERK
Abbreviations: BMP, bone morphogenic
protein; BMPR, bone morphogenic
protein receptor; ERK, extracellular
signal regulated kinase; IL, interleukin;
JAK, Janus kinases; MAPK, mitogen
activated protein kinase; STAT, signal
transducers and activaters of
transcription; TF sat, transferrin
saturation; TfR1, transferrin receptor 1;
TfR2, transferrin receptor 2.
Hepatocyte
Muckenthaler MU. Cell Metab. 2008;8:1-3.
Graphic courtesy of Dr. P. Brissot.
IL6
HFE
SMADs
SMAD
Membrane
Cytosol
STAT3 /JAK
Hepcidin-mRNA
+
Nucleus
Iron-Refractory Iron-Deficiency Anaemia
(IRIDA)—Hepcidin Overproduction
1
Matriptase-2
(TMPRSS6)
mutations
1
Matriptase-2
mutations increase
hepcidin synthesis
in the liver
2
Hepcidin increase
targets the
duodenum and
spleen
3
Duodenal absorption of iron
decreases
4
Splenic iron released into
circulation is decreased
5
Plasma iron concentration
decreases, leading to anaemia
Finberg KE, et al. Nat Genet. 2008;40:569-571.
Hepcidin
2
Iron
5
3
4
Effect of Matriptase-2 Deficiency on Hepcidin Regulation
Plasma
+
BMP
BMP6
HJV
HJV
BMPR
BMPR
Matriptase-2
Tf
Sat
TfR2
TfR2
HFE
HFE
TfR1
TfR1
Membrane
+
SMAD
SMADs
Cytosol
Hepcidin-mRNA
+
Hepatocyte
Nucleus
Ramsay AJ, et al. Haematologica. 2009;94:840-849. Graphic courtesy of Dr. P. Brissot.
Outline
Part 1: Hepcidin as the key hormone of iron
regulation
Part 2: Hepcidin in different human disorders
•
Iron disorders related to hepcidin deficiency
•
Iron disorders related to hepcidin overproduction
•
Other disorders associated with hepcidin
imbalance1,2
1. Origa R, et al. Haematologica. 2007;92:583-588. 2. Kroot JJ, et al. Haematologica. 2009;94:885-887.
Iron Overload Diseases
Sideroblastic anaemias
Thalassaemias
Sickle cell disease
Rare anaemias
Anaemia
Iron Overload
Iron Overload Diseases
Sideroblastic anaemias
Thalassaemias
Sickle cell disease
Rare anaemias
Anaemia
Dyserythropoiesis
Hepcidin
Graphic courtesy of Dr. P. Brissot.
Iron Overload
Effect of Dyserythropoiesis
on Body Iron Regulation
Dyserythropoiesis
Hepcidin
Iron
Abbreviation: GDF, growth differentiation factor.
Tanno T, et al. Nat Med. 2007;13:1096-1101.
Effect of Hypoxia on Body Iron
Regulation
Hypoxia
Hepcidin
Iron
Abbreviation: HIF, hypoxia inducible factor.
Peyssonnaux C, et al. J Clin Invest. 2007;117:1926-1932.
Effect of Nonhaematologic Conditions
on Body Iron
Iron
Effect of Alcohol on Body Iron Regulation
Hepcidin
Iron
Abbreviation: ROS, reactive oxygen species.
Harrison-Findik DD. World J Gastroenterol. 2007;13:4925-4930.
Effect of Polymetabolic Syndrome on
Body Iron Regulation1,2
Hepcidin
Iron
1. Barisani D, et al. J Hepatol. 2008;49:123-133. 2. Ruivard M, et al. J Hepatol. 2009;50:1219-1225.
Effect of Hepatitis C Virus Infection on
Body Iron Regulation
Hepcidin
Hepatitis C
Virus
Iron
Nishina S, et al. Gastroenterology. 2008;134:226-238.
Conclusions
• Hepcidin is the key hormone regulating iron metabolism
• Hepatic hepcidin production is regulated by iron load
– Decreased by iron deficiency
– Increased by iron excess
• Plasma hepcidin targets enterocytes and macrophages
– Increased levels lead to decreased entry of iron into the plasma
(and vice versa)
• Decreased hepcidin can be of genetic or acquired origin
– Genetic: haemochromatosis type 1, 2, 3
– Acquired: dyserythropoiesis, hypoxia, alcoholism, hepatitis C
• Increased hepcidin can be of genetic or acquired origin
– Genetic: IRIDA
– Acquired: inflammation, polymetabolic syndrome
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