Original ResearchBasic and TranslationalāLiverIron Regulation of Hepcidin Despite Attenuated Smad1,5,8 Signaling in Mice Without Transferrin Receptor 2 or Hfe
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Animal Care
Hfe knockout mice33 and Tfr2Y245X mice34 were bred to uniformity on an FVB background for more than 7 generations. The Tfr2Y245X mice have no detectable Tfr2 or truncated form of the protein in hepatocellular membrane preparations and are a functional knockout.34 These 2 mouse lines were crossed with each other and bred to homozygosity for each mutant allele. Colonies were maintained as homozygotes for each allele individually (hereafter referred to as Hfe mice or Tfr2 mice) and as compound
Elevated Bmp6 mRNA Expression is Associated With Hepatic Iron Loading in Mice With Loss of Hfe and/or Tfr2
Functional loss of Hfe or Tfr2 is known to result in inappropriately low hepatic expression of hepcidin and consequent iron overload. Several lines of evidence suggest that up-regulation of Bmp6 contributes to iron-dependent regulation of hepcidin. We measured the hepatic expression of Bmp6 mRNA in Hfe, Tfr2, and Hfe/Tfr2 mice to assess if the decreased hepcidin expression could be attributed to decreased hepatic Bmp6 expression. To provide a comparison group for the degree of hepatic iron
Discussion
The normal relationship between body iron status and liver hepcidin expression requires the action of several identified genes, including HFE, TFR2, HJV, BMP6, and SMAD4.26, 37 Mutations in any one of these genes generate the classic HH phenotype, that is, excess dietary iron absorption, elevated serum iron concentrations, hepatocellular iron loading, and macrophage iron sparing.1, 2 TFR2 is the only one of these gene products known to directly interact with an iron-containing protein, that is,
Acknowledgments
The authors thank Rosemary O'Neill for excellent technical assistance.
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2021, Seminars in HematologyCitation Excerpt :They signal through BMP receptor complexes containing type I receptors (Activin receptor-like kinase ALK3 homodimers or ALK2/3 heterodimers), type II receptors (Activin A Receptor Type 2A ACVR2A and/or BMPR2) and the co-receptor Hemojuvelin HJV [50-52]. Hemochromatosis gene HFE and Transferrin receptor 2 (TfR2) also participate in this signalling complex. [53-56]. TfR2 participation in this receptor complex depends on blood transferrin saturation (Tsat), ensuring that hepcidin transcription is enhanced when Tsat is high and suppressed when Tsat is low [54-56].
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Conflicts of interest The authors disclose no conflicts.
Funding Supported by National Institutes of Health grants (R01 DK063016 to R.E.F., K08 DK075846 to J.L.B., and R01 DK069533 and R01 DK071837 to H.Y.L.) and a Claflin Distinguished Scholar Award from the Massachusetts General Hospital (to J.L.B).