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New Protein!!! Hepcidin

New Protein!!! Hepcidin. Objectives. Describe the processes involved in iron metabolism by the body Discuss the role of hepcidin in iron metabolism Describe diseases of hepcidin deficiency. Review of Iron Metabolism. What I learned (Way back when!!).

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New Protein!!! Hepcidin

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  1. New Protein!!! Hepcidin

  2. Objectives • Describe the processes involved in iron metabolism by the body • Discuss the role of hepcidin in iron metabolism • Describe diseases of hepcidin deficiency

  3. Review of Iron Metabolism What I learned (Way back when!!)

  4. http://www.youtube.com/watch?v=qRVGdv-DGEQ

  5. Detailed Look at Iron Metabolism • Nothing is a simple as it first appears!!

  6. Normal Iron Metabolism • Dietary Iron • Once in the intestines, reduced from Ferric (Fe3+) to Ferrous (Fe2+) • This happens on the lumen side of the proximal small intestines • Ferrous iron is transported into the enterocyte by DMT1 • Divalent metal transporter 1

  7. Dietary heme iron (meat) is transported directly into the enterocyte by an unknown transporter and released from the heme molecule inside of the enterocyte

  8. Iron can be stored within the enterocyte as ferritin or • Transferred across the basolateral membrane to the plasma by transport protein ferroportin1 and MTP1 • Requires oxidation of Ferrous to Ferric by hephaestin.

  9. Transport proteins • DMT1 • Transports from lumen into enterocyte • Ferroportin1, MTP1 • Transports from the enterocyte to circulation

  10. Macrophages recycle iron from erythrocytes • Phagocytize • Lyse • Extract iron from hemoglobin • Using heme oxygenase

  11. Macrophages • Transport of iron across vacuolar membranes into the cytoplasm probably involves DMT1 • In the cytoplasm, iron is stored bound to ferritin

  12. Other cells • Import iron using transferrin receptors (TfRs) • Capture and endocytose diferric transferrin and then use low vacuolar pH to strip the iron from the transferrin-TfR complex

  13. Export of Iron • Ferroportin • Sole exporter of iron in all these cell types • Requires a ferroxidase to deliver iron to transferrin • Enterocytes – hephaestin • Macrophages - ceruloplasmin

  14. Hepcidin directly regulates the expression of ferroportin on cell membranes

  15. Hepcidin directly binds to ferroportin • The binding of hepcidin causes ferroportin to be internalized and degraded • This renders it useless in transporting iron

  16. . Ganz T , Nemeth E Am J Physiol Gastrointest Liver Physiol 2006;290:G199-G203 ©2006 by American Physiological Society

  17. Enterocytes may absorb iron from the gut, but then cannot release it to circulation (transferrin) • Enterocytes are short-lived (2-3 days) • Shed form the villi and ferritin is lost

  18. Balance of absorpiton and storage • Crypt Cells • Proximal small intestines • Precursor cells for absorptive enterocytes • Sense iron needs of the body • Programmed as they mature into enterocytes to express the needed levels of the transport proteins (DMT1 and ferroportin1)

  19. Proposed steps in hepcidin regulation of iron homeostasis. Fleming R E , Sly W S PNAS 2001;98:8160-8162 ©2001 by The National Academy of Sciences

  20. Hepcidin determines whether iron is delivered to plasma transferrin • OR • Removed from the body with the shed enterocytes

  21. When Body Iron Stores Are High • The liver produces Hepcidin • It circulates to the small intestines • Causes ferroportin to be internalized, blocking the transfer of iron to transferrin

  22. When Body Iron Stores Are Low • Hepcidin production is suppressed • Ferroportin molecules are present on membranes of enterocytes • They can transport iron to the plasma (transferrin)

  23. Macrophage Recycling of Iron • Hepcidin-ferroportin interaction • In inflammatory states, hepcidin production is high • Ferroportin on macrophage membranes is internalized, blocking iron export • Iron is “trapped” within macrophages

  24. Once iron has entered circulation, there is not a physiologic mechanism for iron loss, except for menstration

  25. Iron in Circulation • Iron is bound to Transferrin • Passes initially to the Liver • Major storage site for Iron • Iron Utilization – Bone Marrow • Iron is taken up on erythrocyte precursors for heme synthesis

  26. Recycled Iron • Heme iron can be produced in the RE macrophages from ingestion of erythrocytes • Macrophages can also take up iron directly from circulation • Macrophage iron is either • Stored as ferritin • Release into plasma (for reutilization)

  27. Liver and RE system are the major sites of mobilization of iron stores

  28. What is Hepcidin? • Peptide hormone • Produced by liver • Discovered 2000 • Appears to regulate iron hemostasis

  29. . Ganz T , Nemeth E Am J Physiol Gastrointest Liver Physiol 2006;290:G199-G203 ©2006 by American Physiological Society

  30. What is Hepcidin? • 25 – amino acid protein • Hepcidin gene codes for a 72-aa preprohepcidin • Prohepcidin – 60-aa • Cleavage site is found at the 25-aa • Active form is hepcidin (25-aa)

  31. Hepcidin Methods • Prohepcidin • ELISA for urine and serum • Validity questionable; no association between prohepcidin levels and iron absorption

  32. Hepcidin Methods • Hepcidin • Competitive serum ELISA • CV 5-19; 12% • DRG International Inc. • Surface enhanced laser desorption-ionization time-of-flight mass spectrometry (SELDI-TOF-MS) • LC-MSMS • Urine immunodot assay

  33. Hereditary Hemochromatosis • Circulating iron levels are high • RE iron stores are low • Intestinal Iron absorption is excessive • (dysregulated) • Saturation of transferrin, ferritin and other iron-binding proteins • Deposition of iron in vital organs

  34. Hereditary Hemochromatosis • Free iron is toxic • Catalyzes the production of reactive oxygen products • Progresses to liver failure, cardiomyopathy, destruction of endocrine gland, damage to joints

  35. Hereditary Hemochromatosis • Most forms of hemochromatosis are due to hepcidin deficiency

  36. Hereditary Hemochromatosis • Classifications • HFE-gene-related (Type I) • Juvenile hemochromatosis (HJV)

  37. HFE-gene-related (Type 1) • Described more than 100 years ago • Bronze diabetes • Common among western Europeans • Gene at HLA-A3 locus on chromosome 6 • Named HFE gene • Two common mutations can occur that result in HH

  38. Type 1 • Men more frequently affected than women • Autosomal recessive • HFE gene mutation may be favored by natural selection • Enhanced uptake of iron in iron-poor diets • Minimizes the risk of iron-deficiency anemia

  39. Juvenile Hemochromatosis (HJV) • Caused by hemojuvelin mutations (type 2A) • Or • Mutations that disrupt the hepcidin gene (HAMP) (Type 2B)

  40. Hemojuvelin • Protein expressed in liver, skeletal muscle, and heart muscle • Membrane hemojuvelin modulates the iron regulator hepcidin

  41. Hallmark of Juvenile hemochromatosis is low hepcidin activity

  42. Genetic Testing for Hemochromatosis • http://www.youtube.com/watch?v=Wx6EXTvaDUE&feature=related

  43. Anemia of Inflammation • Circulating iron levels are low • Transferrin levels low to normal • RE stores are high (high ferritin) • Intestinal iron absorption is decreased

  44. Anemia of Inflammation • Clinical Conditions • Rheumatologic autoimmune diseases • Malignancies • Infections • Inflammatory Bowel Disease • Common features • Inflammatory cytokines (IL-6) • Tumor necrosis factror-alpha (TNF-alpha) • Bone morphogenic protein (BMP)

  45. Anemia of Inflammation • IL-6 and BMP have been shown to raise hepcidin production in mice • Inhibiting iron release into the blood stream from enterocytes and macrophages

  46. Anemia of Inflammation • It is thought that during infection if body iron stores are decreased, iron will be “unavailable” to the invading bacteria • Studies have shown that hepcidin production increased by lipopolysaccharides and monokines from monocytes exposed to lipopolysaccharides

  47. Anemia of Inflammation • Traditional therapies for AOI to treat the anemia include high doses of erythropoietin and iron therapy • AOI is generally not responsive to oral iron intake because absorption is blocked by increased hepcidin levels • Bone Marrow is less responsive to stimulation. • Parenteral iron administration may be required to improve serum iron levels

  48. Anemia of Inflammation • New methods of cytokine blockade • TNF-alpha blockade is currently in use for rheumatoid arthritis • New therapies aimed at blocking hepcidin-mediated anemia are currently being studied in animal models • Anti-hepcidin antibodies

  49. Anemia of Inflammation • IL-6 strongly induces hepcidin production

  50. Anemia of Inflammation • Hepcidin production is increased up to 100-fold • Iron is sequestered in macrophages

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