Transcript The role of hepcidin in systemic iron regulation
Molecular Pathophysiology of Iron Disorders
Tomas Ganz, PhD, MD Chaim Hershko, MD Slide 1 of 18
Iron Economy
2400 mg 3- 4mg 1000 mg
With permission from Pietrangelo A.
N Engl J Med
. 2004;350:2383-2397.
Slide 2 of 18
Iron Concentration in Plasma Is Regulated
Men Women Range 2.5% –97.5% (μM/L) 13.4
–31.3 μM/L 11.6
–29.5 μM/L Too much iron = tissue and organ damage Too little iron = cellular dysfunction, anaemia Lentner C (ed). Geigy Scientific Tables, Vol 3. Basel: Ciba-Geigy,1984.
Slide 3 of 18
Hepcidin —An Iron-Regulatory and Host Defense Peptide Hormone
Hepcidin 50 m g IP/mouse
Time (hours)
With permission from Rivera S, et al.
Blood.
2005;106:2196-2199.
24 48 72 96
Slide 4 of 18
Ferroportin
• 12 (or 10) transmembrane segment protein • The only cellular iron exporter in vertebrates • Present in the macrophages, duodenum, hepatocytes, and the placenta
45 61 115 127 203 206 324 343 393 450 512 518 23 80 96 152 186 228 307 362 374 471 493 537 N
Donovan A, et al.
Nature
. 2000;403:776-781. McKie AT, et al.
Mol Cell.
Abboud S, et al.
J Biol Chem
. 2000;275:19906-19921.
Graphic courtesy of Tomas Ganz, PhD, MD.
2000;5:299-309.
C
Slide 5 of 18
How Hepcidin Regulates Iron Spleen Liver Hepcidin Fpn Fpn Plasma Fe-Tf Fpn Bone marrow and other sites of iron usage Duodenum
Slide 6 of 18 Nemeth E, et al.
Science.
2004;306:2090-2093.
Courtesy of Tomas Ganz, PhD, MD, and Elizabeta Nemeth, MD.
Low Hepcidin Iron uptake ferritin Fpn High Hepcidin Iron uptake
Iron-exporting cells (duodenal enterocytes, macrophages, hepatocytes)
ferritin Fpn X hepcidin Fe Iron release into plasma
Nemeth E, et al.
Science.
2004;306:2090-2093.
Courtesy of Tomas Ganz, PhD, MD, and Elizabeta Nemeth, MD.
Fe Slide 7 of 18
Diseases of Hepcidin Dysregulation Iron Normal homeostasis Hepcidin Hereditary haemochromatosis Iron-loading Anaemias Anaemia of Inflammation Iron-refractory iron-deficiency anaemia Hepcidin-secreting tumors
Ganz T.
J Am Soc Nephol
. 2007;18:394-400.
Ganz T, Nemeth E.
Am J Physiol Gastrointest Liver Physiol
. 2006;290:G199-G203.
Courtesy of Tomas Ganz, PhD, MD.
Slide 8 of 18
Hereditary Haemochromatosis (Common) HFE TfR2 HJV
Hepcidin deficiency, absolute or relative
Liver Spleen Plasma Fe-Tf RBC Duodenum
Piperno A, et al.
Blood
. 2007;110:4096-4100. Papanikolaou G, et al.
Blood.
Nemeth E, et al.
Blood
.2005;105:1803-1806.
Courtesy of Tomas Ganz, PhD, MD, and Elizabeta Nemeth, MD.
Bone marrow
2005;105:4103-4105. Slide 9 of 18
Hereditary Haemochromatosis (Rare) HFE TfR2 HJV Liver Spleen
Ferroportin resistance to Hepcidin
Duodenum
Fernandes A, et al.
Blood
. 2008; in press.
Courtesy of Tomas Ganz, PhD, MD, and Elizabeta Nemeth, MD.
Plasma Fe-Tf RBC Bone marrow
Slide 10 of 18
Iron-loading Anaemias (
thal…)
Liver Spleen
Hepcidin deficiency
Plasma Fe-Tf RBC Duodenum Erythroid Signal Bone marrow
Nemeth E, Ganz T.
Haematologica
. 2006;91:727-732. Pak M, et al.
Blood.
2006;108:3730-3735. Papanikolaou G, et al.
Blood.
2005;105:4101-4105. Tanno T, et al.
Nat Med.
2007;13;1096-1101.
Courtesy of Tomas Ganz, PhD, MD, and Elizabeta Nemeth, MD.
Slide 11 of 18
Anaemia of Inflammation
Inflammation Liver Spleen Duodenum
Nemeth E, et al.
Blood
. 2003;101:2461-2463. Nemeth E, et al.
J Clin Invest
. 2004;113:1271-1276.
Courtesy of Tomas Ganz, PhD, MD, and Elizabeta Nemeth, MD.
Plasma Fe-Tf RBC Bone marrow
Slide 12 of 18
Iron-Refractory Iron-Deficiency Anaemia (IRIDA)
• Iron deficiency despite adequate or increased iron intake • Partially corrected by parenteral iron • High hepcidin similar to anaemia of inflammation • Mutations in hepcidin-regulatory protease matriptase-2 (TMPRSS6) Slide 13 of 18 Finberg KE, et al.
Nat Genet
. 2008;40:569-571. Du X, et al.
Science
. 2008;320:1088-1092.
Unfinished Business…
• How does extracellular iron regulate hepcidin?
– Current model: holotransferrin + transferrin receptor 2 + transferrin receptor 1 + HFE + haemojuvelin + BMP receptor transcription of hepcidin • How do intracellular iron stores regulate hepcidin?
– Iron-regulatory proteins or other intracellular iron sensors?
• How does matriptase-2 (TMPRSS6) participate in hepcidin regulation?
Slide 14 of 18
Mechanisms Regulating Hepcidin Production
• Iron-driven – Increased by high transferrin saturation and decreased by low plasma iron – TMPRSS6: iron deficiency-driven suppression of hepcidin expression?
• Erythropoiesis-driven – GDF15 suppression of hepcidin • Inflammation-driven – Independent of iron- and erythropoiesis-driven mechanisms – Triggered by IL-6 and other cytokines Slide 15 of 18
Are There Compensatory Mechanisms That Limit Damage?
• Hereditary haemochromatosis: surprising lack of severe infections despite harmful effects of excess iron on bacterial infections; cytokine driven increased hepcidin?
• Thalassaemia major: iron-driven increase of hepcidin production, limiting iron absorption?
• Although compensatory mechanisms may limit possible damage to the organism, they are insufficient to prevent it Slide 16 of 18
Mechanisms of Iron Homeostasis
• Intracellular – Dominated by the IRE-IRP mechanism • Extracellular – Dominated by hepcidin/ferroportin interactions • Intracellular and extracellular mechanisms may interact Slide 17 of 18
Future Hepcidin-Targeted Therapies
• Limitations – Current therapies are effective and inexpensive; those targeting hepcidin are expected to be onerous and costly • Possible role – Hepcidin agonists and/or antagonists may be useful in treating more-complex disorders, such as beta thalassaemia, iron-loading anaemias, IRIDA, and anaemia of inflammation Slide 18 of 18