Hepcidin Suppression Following Phlebotomy Is Regulated by an Erythropoietic Regulator Found in Serum.

Abstract Increasing erythropoiesis requires a dramatic increase in iron absorption or the release of iron from tissue stores. Since the iron regulatory hormone hepcidin blocks both absorption and release from stores, it is suppressed during erythropoiesis. We have recently shown that hepcidin is primarily suppressed by an erythropoietic regulator rather then anemia, hypoxia, or erythropoietin (Pak et al, Blood, epub/in press). To further understand the regulation of hepcidin during erythropoiesis, we subjected groups of eight mice to phlebotomy and sacrificed them at various time points over 3 weeks. Hepcidin mRNA fell 25-fold by day 2 (p<0.001) and did not begin to rise until day 9. Hemoglobin rose well before hepcidin mRNA began to increase confirming that anemia was not the erythropoietic regulator. Serum iron never fell, excluding this as the erythropoietic regulator. Erythropoietin levels spiked early but returned to normal well before hepcidin. Reticulocyte counts increased shortly after the fall in hepcidin and remained elevated after hepcidin mRNA returned to normal. We therefore postulate that the erythropoietic iron regulator is either made by or in concert with early erythroid progenitor cells. Using primary hepatocytes treated with serum from erythropoietin stimulated or control mice, we also demonstrate that the erythropoietic regulator of hepcidin expression is present in the circulation. Experiments are underway to isolate the erythropoietic regulator of hepcidin from serum.