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The Role of Hepcidin in Systemic Iron Regulation

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The Role of Hepcidin in Systemic Iron Regulation Molecular basis of iron homeostasis and its translation to the clinic Tomas Ganz, PhD, MD Systemic iron homeostasis Liver (storage, recycling) Spleen (recycling, storage) Liver Fe 20-25 mg/day Plasma Erythrocytes Fe-Tf 1-2 mg/day 1 ml of PRBC = 1 mg Fe Bone marrow (usage) Duodenum (absorption) Losses 1-2 mg/day During erythropoietic stimulation Liver (storage, recycling) Spleen (recycling, storage) Liver Fe Plasma Erythrocytes Fe-Tf 1 ml of PRBC = 1 mg Fe Bone marrow (usage) Duodenum (absorption) Losses Erythropoietin During infection/inflammation Liver (storage, recycling) Spleen (recycling, storage) Liver Fe Inflammation Plasma Erythrocytes Fe-Tf 1 ml of PRBC = 1 mg Fe Bone marrow (usage) Duodenum (absorption) Losses Hepcidin—an iron-regulatory peptide hormone • Made in the liver as 84 aa preprohepcidin • Cleaved to 25 aa bioactive hepcidin by furin • Secreted by hepatocytes • Regulates intestinal iron absorption and the distribution of iron to tissues DTHFPICIFCCGCCHRSKCGMCCKT Jordan et al. JBC 2009 Tomas Ganz Hepcidin peptide lowers plasma iron Synthetic hepcidin 50 µg IP/mouse 40 M) 30 20 * * * Serum IronSerum ( * 10 * * 0 0 1 2 3 4 5 6 24 48 72 96 Time (hours) Rivera et al. Blood 2005 Ferroportin • 12 transmembrane segment protein • Found in plants, invertebrates, vertebrates • In vertebrates, the receptor for hepcidin • The only cellular iron exporter known (Donovan et al.) • Present in the macrophages, duodenum, hepatocytes, and the placenta (Donovan et al., McKie et al., Abboud et al.) 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 C Ferroportin is internalized by hepcidin and degraded in lysosomes control + 1 µg/ml hepcidin Nemeth et al. Science 2004 Regulation of intestinal iron absorption Dietary iron uptake Food Dietary iron uptake ferritin ferritin Duodenal enterocytes Fpn Fpn X Blood hepcidin Fe Fe Low hepcidin High hepcidin Regulation of erythrocyte iron recycling Erythrocyte Erythrocyte uptake uptake Macrophages ferritin ferritin Fpn Fpn X Iron release into plasma hepcidin Fe Fe Low hepcidin High hepcidin Hepcidin regulates dietary iron absorption and influx to plasma Liver Spleen Liver hepcidin Fe Fpn hepcidin Fpn Plasma Fe-Tf Erythrocytes Fpn Bone marrow Duodenum Tomas Ganz Signals regulating hepcidin Inflammation Liver Spleen Liver hepcidin Fe Fpn hepcidin Fpn Plasma Erythrocytes Fe-Tf Fpn Iron signals Bone marrow Duodenum Erythropoietic signal Hepcidin excess in anemia of inflammation • Hepcidin-dependent effects – Inflammatory cytokines increase hepcidin and cause Fe trapping in macrophages – Fe restricts hemoglobin synthesis and erythropoiesis is inhibited • Hepcidin-independent effects – Shortened erythrocyte lifespan – Direct suppression of erythropoiesis by cytokines Iron-restricted anemias Inflammation Liver Spleen Plasma hepcidin clearance Fe-Tf RBC Duodenum Bone Kidneys marrow Ablation of hepcidin is beneficial in anemia of inflammation induced by heat-killed Brucella abortus 18 16 hepcidin KO WT 14 saline 12 Brucella 10 8 Hemoglobin (g/dL) 6 0 7d 14d 21d 28d Time Kim et al. Blood 2014 Hepcidin deficiency in β-thalassemia secreted suppressors less hepcidin Fe overload Worse anemia • Failure of red cell precursors to mature into functional RBCs • Anemia, increased erythropoietin • Expansion of immature RBC precursors • Hepcidin-suppressive signal causes hepcidin deficiency Anemia • Increased Fe absorption, Fe overload Rational design of peptide agonists • Strategy for development: structure-function study of hepcidin and ferroportin C N 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 C Hepcidin Ferroportin 25 aa peptide hormone 571 aa protein 4 disulfide bonds 12 transmembrane segments Preza at al. JCI 2011, Ramos et al. Blood 2012 Minihepcidin PR73 Ida-Thr-His-Dpa-bhPro-Arg-Cys-Arg-bhPhe-Ahx- Ida(NHPal)-CONH2 iminodiacetic acid, L-threonine, L-histidine, L-3,3-diphenylalanine, L-β-homoproline, L- arginine, L-cysteine, L-arginine, L-β-homophenylalanine, 6-aminohexanoic acid, iminodiacetic acid palmitylamide (PEG-free) Mouse model of β-thalassemia: minihepcidin improves anemia and decreases iron overload 1600 16 1400 14 p = 0.001 p = 0.0003 1200 12 g/g) 1000 10 800 8 6 600 Liver iron ( iron Liver Hemoglobin (g/dl) Hemoglobin 4 400 2 200 0 0 WT TH3/solvent TH3/MH WT TH3/solvent TH3/MH Mouse/treatment Mouse/treatment M004 (2.65 mg/kg) or solvent was administered 2x weekly SQ x 6 wks C Casu, S. Rivella et al. and Merganser Biotech A search for erythroid factor suppressing hepcidin • Stimulated erythropoiesis in mice by phlebotomy (0.5 ml) or EPO injection (200 U) 4 phlebotomy 2 * p<0.05 EPO ** p<0.01 1 * ***p<0.001 * ** 0.5 mRNA expression *** *** 0.25 *** *** Hamp 0.125 Liver 0.062 CTRL 4h 9h 12h 15h 24h • Gene chip expression profiling of the bone marrow to identify erythroid transcripts that 1) change before the hepcidin suppression and 2) encode secreted proteins Erythroferrone (Erfe) Erythroferrone (Fam132b, CTRP15) TNFα-like Polybasic cleavage sites? Signal sequence Collagen stalk GPP-rich • 50 kD glycoprotein highly expressed in erythropoietin-stimulated erythroblasts Erfe knockout mice do not suppress hepcidin in response to bleeding • Erfe1+/+, +/- and -/- mice were phlebotomized (0.5 ml) Hepcidin mRNA Hemoglobin recovery * p<0.05 ** p<0.01 *** p<0.001 Dose-response for mouse erythroferrone on hepatocytes 1.0 EC50 = 7 ng/ml ~ 140 pM 0.8 0.6 0.4 Fractional response Fractional 0.2 0.0 0 1 3 10 30 100 300 1000 Conc ng/ml mErfe (24-340) Mouse model of β-thalassemia: Ablation of Erfe reverses hepcidin suppression and improves iron overload Hepcidin Liver iron 200 *** 300 *** *** *** * 150 200 100 50 100 serum hepcidin (ng/mL) 0 g non-heme iron / g liver wet weight 0 WT WT Th3/+ Th3/+ Erfe-/-Th3/+ Erfe-/-Th3/+ Development of new treatments • Prevent iron overload and improve erythropoiesis in β-thalassemia – minihepcidins (hepcidin agonists) – erythroferrone antagonists • Release sequestered iron in anemia of inflammation and anemia of chronic kidney disease – hepcidin antagonists – erythroferrone agonists • UCLA licensed the intellectual property related to minihepcidin and erythroferrone to two startup companies for drug development Key contributors Ella Nemeth: Piotr Ruchala: Everything Minihepcidin design Airie Kim: León Kautz: Mouse models Erythroferrone of anemia of inflammation .
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