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HFE and ALK3 act in the same signaling pathway

L. Traeger, J. Schnittker, DY. Dogan, D. Oguama, T. Kuhlmann, MU. Muckenthaler, J. Krijt, EI. Urzica, AU. Steinbicker

. 2020 ; 160 (-) : 501-505. [pub] 20200827

Language English Country United States

Document type Journal Article, Research Support, Non-U.S. Gov't

Persistent link   https://www.medvik.cz/link/bmc21019809

Hepcidin deficiency leads to iron overload by increased dietary iron uptake and iron release from storage cells. The most frequent mutation in Hfe leads to reduced hepcidin expression and thereby causes iron overload. Recent findings suggested that HFE activates hepcidin expression predominantly via the BMP type I receptor ALK3. Here, we investigated whether HFE exclusively utilizes ALK3 or other signaling mechanisms also. We generated mice with double deficiency of Hfe and hepatocyte-specific Alk3 and compared the iron overload phenotypes of these double knockout mice to single hepatocyte-specific Alk3 deficient or Hfe knockout mice. Double Hfe-/-/hepatic Alk3fl/fl;Alb-Cre knockouts develop a similar iron overload phenotype compared to single hepatocyte-specific Alk3 deficient mice hallmarked by serum iron levels, tissue iron content and hepcidin levels of similar grades. HFE protein levels were increased in Alk3fl/fl;Alb-Cre mice compared to Alk3fl/fl mice, which was caused by iron overload - and not by Alk3 deficiency. The data provide evidence by genetic means that 1. HFE exclusively uses the BMP type I receptor ALK3 to induce hepcidin expression and 2. HFE protein expression is induced by iron overload, which further emphasizes the iron sensing function of HFE.

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$a Hepcidin deficiency leads to iron overload by increased dietary iron uptake and iron release from storage cells. The most frequent mutation in Hfe leads to reduced hepcidin expression and thereby causes iron overload. Recent findings suggested that HFE activates hepcidin expression predominantly via the BMP type I receptor ALK3. Here, we investigated whether HFE exclusively utilizes ALK3 or other signaling mechanisms also. We generated mice with double deficiency of Hfe and hepatocyte-specific Alk3 and compared the iron overload phenotypes of these double knockout mice to single hepatocyte-specific Alk3 deficient or Hfe knockout mice. Double Hfe-/-/hepatic Alk3fl/fl;Alb-Cre knockouts develop a similar iron overload phenotype compared to single hepatocyte-specific Alk3 deficient mice hallmarked by serum iron levels, tissue iron content and hepcidin levels of similar grades. HFE protein levels were increased in Alk3fl/fl;Alb-Cre mice compared to Alk3fl/fl mice, which was caused by iron overload - and not by Alk3 deficiency. The data provide evidence by genetic means that 1. HFE exclusively uses the BMP type I receptor ALK3 to induce hepcidin expression and 2. HFE protein expression is induced by iron overload, which further emphasizes the iron sensing function of HFE.
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$a Schnittker, J $u Department of Anesthesiology, Intensive Care and Pain Medicine, University Hospital Muenster, University of Muenster, Muenster, Germany. Electronic address: j_schn55@uni-muenster.de
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$a Dogan, D Y $u Department of Anesthesiology, Intensive Care and Pain Medicine, University Hospital Muenster, University of Muenster, Muenster, Germany. Electronic address: d_doga04@uni-muenster.de
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$a Oguama, D $u Department of Anesthesiology, Intensive Care and Pain Medicine, University Hospital Muenster, University of Muenster, Muenster, Germany. Electronic address: david.oguama@ukmuester.de
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$a Kuhlmann, T $u Institute of Neuropathology, University Hospital Muenster, University of Muenster, Muenster, Germany. Electronic address: tanja.kuhlmann@ukmuenster.de
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$a Muckenthaler, M U $u Department of Pediatric Oncology, Hematology and Immunology, Molecular Medicine Partnership (MMPU), European Molecular Biology Laboratory (EMBL), University of Heidelberg, Heidelberg, Germany. Electronic address: martina.muckenthaler@med.uni-heidelberg.de
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$a Krijt, J $u Institute of Pathological Physiology, First Faculty of Medicine, Charles University, Prague, Czech Republic. Electronic address: Jan.Krijt@lf1.cuni.cz
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$a Urzica, E I $u Department of Anesthesiology, Intensive Care and Pain Medicine, University Hospital Muenster, University of Muenster, Muenster, Germany. Electronic address: eurzi_01@uni-muenster.de
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$a Steinbicker, A U $u Department of Anesthesiology, Intensive Care and Pain Medicine, University Hospital Muenster, University of Muenster, Muenster, Germany. Electronic address: Andrea.steinbicker@ukmuenster.de
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