Update on Hepcidin Regulation in Different Disorders

Pierre Brissot, MD

Professor of MedicineLiver Disease Department

University Hospital PontchaillouRennes, France

Outline

Part 1: Hepcidin as the key hormone of ironregulation

Part 2: Hepcidin in different humandisorders

• Iron disorders related to hepcidin deficiency

• Iron disorders related to hepcidin overproduction

• Other disorders associated with hepcidin imbalance

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.

Hepcidin General Features

• “Hep” for hepatic and “cidin” for antimicrobial activity1

• 25-amino-acid protein (derived from an84-amino-acid precursor)2,3

• Coded by the HAMP gene (chromosome 19)3,4

• Mainly produced by hepatocytes4,5

Body Iron Regulation by Hepcidin

11 Body iron decrease lowers hepcidin synthesis in the liver

33 Duodenal absorption of iron increases

44 Splenic iron is released into the circulation

55 Iron concentration in plasma increases, leading to restoration of iron balance

Hepcidin deficiency targets the duodenum and spleen

22

Iron Iron DeficiencyDeficiency Hepcidin

11

22

33

44IronIron

Ganz T, et al. Am J Physiol Gastrointest Liver Physiol. 2006;290:G199-G203.

55

Hepcidin–Cellular Targets and Mechanism of Action

11

2233

55

Cell (enterocyte and macrophage)

Plasma

Hepcidin circulates in plasma

22

33 Hepcidin binds to ferroportin on the cell’s surface

44 Internalization

Ferroportin degradation

55

Decreased ferroportin exports less iron to plasma

66

Ferroportin exports iron from cell to plasma

11

Brissot P, et al. Blood Rev. 2008;22:195-210.

44

66

HEPCIDIN

Ferroportin

Regulation of Hepcidin Transcription1-3

BMP6

BMPR

SMADs

HJV

TfR2

TfR1HFE

Tf Sat

Plasma

Hepatocyte

Nucleus

Membrane

Cytosol

MAPK/ERK

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.

11

22

33

44

55

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

Regulation of Hepcidin Transcription–Hypothetical1-3

Hepcidin-mRNA

BMP

BMPR

SMAD

HJV

TfR2

TfR1HFE

BMP6

BMPR

SMADs

HJV

TfR2

TfR1HFE

Tf SatPlasma

Hepatocyte

Nucleus

Membrane

Cytosol

MAPK/ERK

11

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.

22

Hepcidin-mRNA

BMP

BMPR

SMAD

HJV

TfR2

TfR1HFE

BMP6

BMPR

SMADs

HJV

TfR2

TfR1HFE

Tf SatPlasma

Hepatocyte

Nucleus

Membrane

Cytosol

Matriptase-2

22

11

Regulation of Hepcidin by Matriptase-2 Hypothetical

Ramsay AJ, et al. Haematologica. 2009;94:840-849. Graphic courtesy of Dr. P. Brissot.

–

Outline

Part 1: Hepcidin as the key hormone of ironregulation

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

11 HFE or non-HFE mutations decrease hepcidin synthesis in the liver

33 Duodenal absorption of iron increases

44 Splenic iron is released into the circulation

55 Iron concentration in plasma strongly increases

Hepcidin deficiency targets the duodenum and spleen

22

HFE HFE (type1) (type1) or non-or non-HFE HFE (type 2 or 3) (type 2 or 3) mutationsmutations

Hepcidin11

22

33

44

IronIron55

66

66Increased plasma iron produces parenchymal iron deposition

Brissot P, et al. Blood Rev. 2008;22:195-210.

Quantitative Defect in Hepcidin-Ferroportin Interaction—Types 1, 2, and 3

Haemochromatosis

11

2233

55

Cell (enterocyte and macrophage)

Plasma

Decreased hepcidin circulates in plasma

22

33 Decreased hepcidin binds to ferroportin on the cell’s surface

44 Internalization

Decreased ferroportin degradation

55

Increased ferroportin exports more iron to plasma

66

Ferroportin exports iron from cell to plasma

11

Brissot P, et al. Blood Rev. 2008;22:195-210.

44

66

Type 4B Haemochromatosis—Qualitative Hepcidin DefectHepcidin Resistance

11

2233

55

Cell (enterocyte and macrophage)

Plasma

Normal hepcidin level circulating in plasma

22

33 Defect in hepcidin binding to ferroportin

44 Decreased ferroportin degradation

Increased ferroportin

55

Increased ferroportin activity exports more iron to plasma

66

Mutated ferroportin

11

Brissot P, et al. Blood Rev. 2008;22:195-210.

44

66

Outline

Part 1: Hepcidin as the key hormone of ironregulation

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

11 Inflammation increases hepcidin synthesis in the liver

33 Duodenal absorption of iron decreases

44 Splenic iron released into circulation is decreased

Hepcidin increase targets the duodenum and spleen

22

InflammationInflammation Hepcidin11

22

33

44

IronIron66

55

66Plasma iron concentration decreases, leading to anaemia

Brissot P, et al. Blood Rev. 2008;22:195-210.

55 Overloaded macrophages

55

Hepcidin-mRNA

BMP

BMPR

SMAD

HJV

TfR2

TfR1HFE

BMP6

BMPR

SMADs

HJV

TfR2

TfR1HFE

HepatocyteNucleus

MembraneCytosol

MAPK/ERKAbbreviations: 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.

InflammationInflammation

IL6IL6

STAT3 /JAK

+

Muckenthaler MU. Cell Metab. 2008;8:1-3.Graphic courtesy of Dr. P. Brissot.

IL6 Mediation of Hepcidin in Inflammation

Iron-Refractory Iron-Deficiency Anaemia (IRIDA)—Hepcidin Overproduction

11 Matriptase-2 mutations increase hepcidin synthesis in the liver

33 Duodenal absorption of iron decreases

44 Splenic iron released into circulation is decreased

Hepcidin increase targets the duodenum and spleen

22

Hepcidin11

22

33

44IronIron

5555

Plasma iron concentration decreases, leading to anaemia

Matriptase-2 Matriptase-2 (TMPRSS6) (TMPRSS6) mutationsmutations

Finberg KE, et al. Nat Genet. 2008;40:569-571.

Hepcidin-mRNA

BMP

BMPR

SMAD

HJV

TfR2

TfR1HFE

BMP6

BMPR

SMADs

HJV

TfR2

TfR1HFE

Tf Sat

Plasma

Hepatocyte

Nucleus

Membrane

Cytosol

Matriptase-2

+

+

+

Effect of Matriptase-2 Deficiency on Hepcidin Regulation

Ramsay AJ, et al. Haematologica. 2009;94:840-849. Graphic courtesy of Dr. P. Brissot.

Outline

Part 1: Hepcidin as the key hormone of ironregulation

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

Iron Overload

Anaemia

Iron Overload Diseases

Graphic courtesy of Dr. P. Brissot.

Sideroblastic anaemias

Thalassaemias

Sickle cell disease

Rare anaemias

Iron Overload

Dyserythropoiesis

Hepcidin

Anaemia

Effect of Dyserythropoiesis on Body Iron Regulation

Hepcidin

IronIron

DyserythropoiesisDyserythropoiesis

Tanno T, et al. Nat Med. 2007;13:1096-1101.Abbreviation: GDF, growth differentiation factor.

GDF15

Effect of Hypoxia on Body Iron Regulation

HepcidinHypoxiaHypoxia

Abbreviation: HIF, hypoxia inducible factor.

HIF

Peyssonnaux C, et al. J Clin Invest. 2007;117:1926-1932.

IronIron

Effect of Nonhaematologic Conditions on Body Iron

Iron

Effect of Alcohol on Body Iron Regulation

Hepcidin

Abbreviation: ROS, reactive oxygen species.

ROS

ROS

Harrison-Findik DD. World J Gastroenterol. 2007;13:4925-4930.

IronIron

Effect of Polymetabolic Syndrome on Body Iron Regulation1,2

Hepcidin

IronIron

ROS

ROS

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

ROS

ROS

Hepatitis C Virus

Nishina S, et al. Gastroenterology. 2008;134:226-238.

IronIron

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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