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Update on Hepcidin Regulation in Different Disorders

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

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Update on Hepcidin Regulation in Different Disorders

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  1. Update on Hepcidin Regulation in Different Disorders Pierre Brissot, MD Professor of Medicine
Liver Disease DepartmentUniversity Hospital PontchaillouRennes, France

  2. Outline Part 1: Hepcidin as the key hormone of iron regulation Part 2: Hepcidin in different humandisorders Iron disorders related to hepcidin deficiency Iron disorders related to hepcidin overproduction Other disorders associated with hepcidin imbalance

  3. 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 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.

  4. Body iron decrease lowers hepcidin synthesis in the liver 1 Hepcidin deficiency targets the duodenum and spleen 2 Duodenal absorption of iron increases 3 Splenic iron is released into the circulation 4 Iron concentration in plasma increases, leading to restoration of iron balance 5 Body Iron Regulation by Hepcidin Iron Deficiency 1 Hepcidin 2 Iron 4 5 3 Ganz T, et al. Am J Physiol Gastrointest Liver Physiol. 2006;290:G199-G203.

  5. Ferroportin exports iron from cell to plasma 1 Hepcidin circulates in plasma 2 Hepcidin binds to ferroportin on the cell’s surface 3 Internalization 4 Ferroportin degradation 5 Decreased ferroportin exports less iron to plasma 6 Hepcidin–Cellular Targets and Mechanism of Action Cell (enterocyte and macrophage) F F 5 H 4 F 1 F F 6 H H 3 Plasma 2 Brissot P, et al. Blood Rev. 2008;22:195-210.

  6. Ferroportin HEPCIDIN

  7. Tf Sat BMP6 TfR1 TfR2 BMPR Regulation of Hepcidin Transcription1-3 Plasma 4 HJV 1 HFE 2 Membrane 5 MAPK/ERK SMADs Cytosol Hepcidin-mRNA 3 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. 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.

  8. Tf Sat BMP BMP6 TfR1 TfR2 BMPR BMPR Regulation of Hepcidin Transcription–Hypothetical1-3 1 Plasma HJV HJV 2 TfR2 HFE HFE 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.

  9. Regulation of Hepcidin by Matriptase-2 Hypothetical Tf Sat BMP BMP6 TfR1 TfR2 BMPR BMPR 2 Plasma HJV 1 HJV TfR2 HFE TfR1 HFE Matriptase-2 Membrane SMAD SMADs Cytosol Hepcidin-mRNA – Hepatocyte Nucleus Ramsay AJ, et al. Haematologica.2009;94:840-849. Graphic courtesy of Dr. P. Brissot.

  10. 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

  11. HFE or non-HFE mutations decrease hepcidin synthesis in the liver 1 Hepcidin deficiency targets the duodenum and spleen 2 Duodenal absorption of iron increases 3 Splenic iron is released into the circulation 4 Iron concentration in plasma strongly increases 5 Increased plasma iron produces parenchymal iron deposition 6 Types 1, 2, and 3 Haemochromatosis—Quantitative Hepcidin Defect 1 HFE (type1) or non-HFE (type 2 or 3) mutations Hepcidin 6 2 Iron 4 5 3 Brissot P, et al. Blood Rev. 2008;22:195-210.

  12. Ferroportin exports iron from cell to plasma 1 Decreased hepcidin circulates in plasma 2 Decreased hepcidin binds to ferroportin on the cell’s surface 3 Internalization 4 Decreased ferroportin degradation 5 Increased ferroportin exports more iron to plasma 6 Quantitative Defect in Hepcidin-Ferroportin Interaction—Types 1, 2, and 3 Haemochromatosis Cell (enterocyte and macrophage) F F H 5 4 F 1 F F H H 3 6 Plasma 2 Brissot P, et al. Blood Rev. 2008;22:195-210.

  13. Mutated ferroportin 1 Normal hepcidin level circulating in plasma 2 Defect in hepcidin binding to ferroportin 3 Decreased ferroportin degradation 4 Increased ferroportin 5 Increased ferroportin activity exports more iron to plasma 6 Type 4B Haemochromatosis—Qualitative Hepcidin DefectHepcidin Resistance Cell (enterocyte and macrophage) F F 5 4 F 1 F F H H 3 6 Plasma 2 Brissot P, et al. Blood Rev. 2008;22:195-210.

  14. 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.

  15. Inflammation increases hepcidin synthesis in the liver 1 Hepcidin increase targets the duodenum and spleen 2 Duodenal absorption of iron decreases 3 Splenic iron released into circulation is decreased 4 Overloaded macrophages 5 Plasma iron concentration decreases, leading to anaemia 6 Anaemia of Inflammation/Chronic Disease—Hepcidin Overproduction 1 Inflammation Hepcidin 5 2 5 Iron 4 6 3 Brissot P, et al. Blood Rev. 2008;22:195-210.

  16. BMP BMP6 TfR1 TfR2 BMPR BMPR IL6 Mediation of Hepcidin in Inflammation Inflammation HJV HJV TfR2 IL6 HFE HFE TfR1 Membrane Cytosol MAPK/ERK SMADs SMAD 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. STAT3 /JAK Hepcidin-mRNA + Hepatocyte Nucleus Muckenthaler MU. Cell Metab. 2008;8:1-3.Graphic courtesy of Dr. P. Brissot.

  17. Matriptase-2 mutations increase hepcidin synthesis in the liver 1 Hepcidin increase targets the duodenum and spleen 2 Duodenal absorption of iron decreases 3 Splenic iron released into circulation is decreased 4 Plasma iron concentration decreases, leading to anaemia 5 Iron-Refractory Iron-Deficiency Anaemia (IRIDA)—Hepcidin Overproduction 1 Matriptase-2 (TMPRSS6) mutations Hepcidin 2 Iron 4 5 3 Finberg KE, et al. Nat Genet. 2008;40:569-571.

  18. Tf Sat BMP BMP6 TfR1 TfR2 BMPR BMPR Effect of Matriptase-2 Deficiency on Hepcidin Regulation Plasma + HJV HJV TfR2 HFE TfR1 HFE Matriptase-2 + Membrane SMAD SMADs Cytosol Hepcidin-mRNA + Hepatocyte Nucleus Ramsay AJ, et al. Haematologica. 2009;94:840-849. Graphic courtesy of Dr. P. Brissot.

  19. 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.

  20. Iron Overload Diseases Sideroblastic anaemias Thalassaemias Sickle cell disease Rare anaemias Anaemia Iron Overload

  21. Dyserythropoiesis Hepcidin Iron Overload Diseases Sideroblastic anaemias Thalassaemias Sickle cell disease Rare anaemias Anaemia Iron Overload Graphic courtesy of Dr. P. Brissot.

  22. GDF15 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.

  23. HIF 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.

  24. Effect of Nonhaematologic Conditions 
on Body Iron Iron

  25. ROS Effect of Alcohol on Body Iron Regulation Hepcidin Iron Abbreviation: ROS, reactive oxygen species. Harrison-Findik DD. World J Gastroenterol. 2007;13:4925-4930.

  26. ROS 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.

  27. ROS Effect of Hepatitis C Virus Infection on Body Iron Regulation Hepcidin Hepatitis C Virus Iron Nishina S, et al. Gastroenterology. 2008;134:226-238.

  28. 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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