Transferrin is a major determinant of hepcidin expression in hypotransferrinemic mice.

As a central regulator of iron metabolism, hepcidin inhibits dietary iron absorption and macrophage iron recycling. Its expression is regulated by multiple factors including iron availability and erythropoietic activity. To investigate the role of transferrin (Tf) in the regulation of hepcidin expression by these factors in vivo, we employed the hypotransferrinemic (hpx) mouse. These Tf-deficient mice have severe microcytic anemia, tissue iron overload, and hepcidin deficiency. To determine the relationship of Tf levels and erythropoiesis to hepcidin expression, we subjected hpx mutant and control mice to a number of experimental manipulations. Treatment of hpx mice with Tf injections corrected their anemia and restored hepcidin expression. To investigate the effect of erythropoiesis on hepcidin expression, we suppressed erythropoiesis with blood transfusions or myeloablation with chemotherapeutic drugs. Transfusion of hpx animals with wild-type red blood cells led to increased hepcidin expression, while hepcidin expression in myeloablated hpx mice increased only if Tf was administered postablation. These results suggest that hepcidin expression in hpx mice is regulated both by Tf-restricted erythropoiesis and by Tf through a mechanism independent of its role in erythropoiesis.

[1]  Jeffery L. Miller,et al.  Iron Loading and Overloading due to Ineffective Erythropoiesis , 2010, Advances in hematology.

[2]  D. Koeberl,et al.  The Role of Hepatocyte Hemojuvelin in the Regulation of Bone Morphogenic Protein-6 and Hepcidin Expression in Vivo* , 2010, The Journal of Biological Chemistry.

[3]  Charles B. Hall,et al.  Transferrin therapy ameliorates disease in β-thalassemic mice , 2010, Nature Medicine.

[4]  Paolo Ventura,et al.  Bone morphogenetic protein signaling is impaired in an HFE knockout mouse model of hemochromatosis. , 2009, Gastroenterology.

[5]  M. Roth,et al.  BMP/Smad signaling is not enhanced in Hfe-deficient mice despite increased Bmp6 expression. , 2009, Blood.

[6]  Y. T. Lee,et al.  Identification of TWSG1 as a second novel erythroid regulator of hepcidin expression in murine and human cells. , 2009, Blood.

[7]  S. Vaulont,et al.  Cross-talk between the mitogen activated protein kinase and bone morphogenetic protein/hemojuvelin pathways is required for the induction of hepcidin by holotransferrin in primary mouse hepatocytes , 2009, Haematologica.

[8]  L. Zon,et al.  Transferrin-a modulates hepcidin expression in zebrafish embryos. , 2009, Blood.

[9]  H. Tsukamoto,et al.  Interaction of the hereditary hemochromatosis protein HFE with transferrin receptor 2 is required for transferrin-induced hepcidin expression. , 2009, Cell metabolism.

[10]  M. Roth,et al.  Lack of the bone morphogenetic protein BMP6 induces massive iron overload , 2009, Nature Genetics.

[11]  Yin Xia,et al.  BMP6 is a key endogenous regulator of hepcidin expression and iron metabolism , 2009, Nature Genetics.

[12]  Jean Mosser,et al.  Iron regulates phosphorylation of Smad1/5/8 and gene expression of Bmp6, Smad7, Id1, and Atoh8 in the mouse liver. , 2008, Blood.

[13]  N. Andrews,et al.  The transferrin receptor modulates Hfe-dependent regulation of hepcidin expression. , 2008, Cell metabolism.

[14]  M. Fleming.  The regulation of hepcidin and its effects on systemic and cellular iron metabolism. , 2008, Hematology. American Society of Hematology. Education Program.

[15]  T. Ganz,et al.  Effects of plasma transfusion on hepcidin production in human congenital hypotransferrinemia , 2007, Haematologica.

[16]  Elizabeta Nemeth,et al.  Iron transferrin regulates hepcidin synthesis in primary hepatocyte culture through hemojuvelin and BMP2/4. , 2007, Blood.

[17]  S. Goh,et al.  High levels of GDF15 in thalassemia suppress expression of the iron regulatory protein hepcidin , 2007, Nature Medicine.

[18]  T. Ganz,et al.  Suppression of hepcidin during anemia requires erythropoietic activity. , 2006, Blood.

[19]  M. Wessling-Resnick,et al.  Regulation of transferrin receptor 2 protein levels by transferrin. , 2004, Blood.

[20]  M. Loda,et al.  Inappropriate expression of hepcidin is associated with iron refractory anemia: implications for the anemia of chronic disease. , 2002, Blood.

[21]  N. Andrews,et al.  The molecular defect in hypotransferrinemic mice. , 2000, Blood.

[22]  R. Simpson,et al.  Importance of anemia and transferrin levels in the regulation of intestinal iron absorption in hypotransferrinemic mice. , 1999, Blood.

[23]  C. Finch,et al.  Regulators of iron balance in humans. , 1994, Blood.

[24]  S. Buys,et al.  Iron absorption in hypotransferrinemic mice. , 1991, Blood.

[25]  C. Craven,et al.  Tissue distribution and clearance kinetics of non-transferrin-bound iron in the hypotransferrinemic mouse: a rodent model for hemochromatosis. , 1987, Proceedings of the National Academy of Sciences of the United States of America.