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.

• Klíčová slova
• BMP signaling, BMP type I receptor, HFE, Hepcidin, Iron overload,
• MeSH
• hepcidiny * genetika   MeSH
• játra metabolismus   MeSH
• MHC antigeny I. třídy genetika   MeSH
• myši knockoutované MeSH
• myši MeSH
• přetížení železem * genetika   MeSH
• protein hemochromatózy genetika   MeSH
• receptory morfogenetických kostních proteinů typu I MeSH
• signální transdukce MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• Bmpr1a protein, mouse MeSH Prohlížeč
• hepcidiny * MeSH
• Hfe protein, mouse MeSH Prohlížeč
• MHC antigeny I. třídy MeSH
• protein hemochromatózy MeSH
• receptory morfogenetických kostních proteinů typu I MeSH