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The Transferrin Receptor Modulates Hfe-Dependent Regulation of Hepcidin Expression

Schmidt, Paul J. and Toran, Paul T. and Giannetti, Anthony M. and Bjorkman, Pamela J. and Andrews, Nancy C. (2008) The Transferrin Receptor Modulates Hfe-Dependent Regulation of Hepcidin Expression. Cell Metabolism, 7 (3). pp. 205-214. ISSN 1550-4131. PMCID PMC2292811. https://resolver.caltech.edu/CaltechAUTHORS:20170327-141608645

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Abstract

Hemochromatosis is caused by mutations in HFE, a protein that competes with transferrin (TF) for binding to transferrin receptor 1 (TFR1). We developed mutant mouse strains to gain insight into the role of the Hfe/Tfr1 complex in regulating iron homeostasis. We introduced mutations into a ubiquitously expressed Tfr1 transgene or the endogenous Tfr1 locus to promote or prevent the Hfe/Tfr1 interaction. Under conditions favoring a constitutive Hfe/Tfr1 interaction, mice developed iron overload attributable to inappropriately low expression of the hormone hepcidin. In contrast, mice carrying a mutation that interferes with the Hfe/Tfr1 interaction developed iron deficiency associated with inappropriately high hepcidin expression. High-level expression of a liver-specific Hfe transgene in Hfe−/− mice was also associated with increased hepcidin production and iron deficiency. Together, these models suggest that Hfe induces hepcidin expression when it is not in complex with Tfr1.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1016/j.cmet.2007.11.016DOIArticle
http://www.sciencedirect.com/science/article/pii/S1550413107003737PublisherArticle
http://www.sciencedirect.com/science/article/pii/S1550413107003737PublisherSupplemental Data
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2292811/PubMed CentralArticle
ORCID:
AuthorORCID
Bjorkman, Pamela J.0000-0002-2277-3990
Additional Information:© 2008 Elsevier Inc. Received: October 3, 2007. Revised: November 10, 2007. Accepted: November 30, 2007. Published: March 4, 2008. This work was supported by NIH grants R01 DK53813 (N.C.A.) and K01 DK074410 (P.J.S.). We would like to thank F. Costantini for the pBigT vector, P. Soriano for the pROSA26-1 vector, and T. Van Dyke for the pTTR1exV3 vector. We thank M. Thompson and the Children’s Hospital Boston Mental Retardation Research Center Gene Manipulation Facility (NIH grant P30 HD018655) for blastocyst injections and Y. Fujiwara and the Children’s Hospital Boston Center for Molecular Developmental Hematopoiesis (NIH grant P30 DK49216-14) for blastocyst injections and pronuclei microinjections. Finally, we thank A. Donovan and C. Roy for technical advice and helpful suggestions, K. Roberts and T. Bartnikas for reviewing the manuscript, and members of the Andrews and Fleming laboratories for helpful discussions. A.M.G. and P.J.B. designed the Tfr1 mutations and analyzed the protein interactions in vitro. P.J.S. and N.C.A. conceived and designed the mouse experiments, analyzed the data, and wrote the manuscript. P.T.T. maintained the mouse colony and assisted in phenotyping the animals.
Funders:
Funding AgencyGrant Number
NIHR01 DK53813
NIHK01 DK074410
NIHP30 HD018655
NIHP30 DK49216-14
Subject Keywords:HUMDISEASE
Issue or Number:3
PubMed Central ID:PMC2292811
Record Number:CaltechAUTHORS:20170327-141608645
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20170327-141608645
Official Citation:Paul J. Schmidt, Paul T. Toran, Anthony M. Giannetti, Pamela J. Bjorkman, Nancy C. Andrews, The Transferrin Receptor Modulates Hfe-Dependent Regulation of Hepcidin Expression, Cell Metabolism, Volume 7, Issue 3, 5 March 2008, Pages 205-214, ISSN 1550-4131, http://dx.doi.org/10.1016/j.cmet.2007.11.016. (http://www.sciencedirect.com/science/article/pii/S1550413107003737)
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:75432
Collection:CaltechAUTHORS
Deposited By: Ruth Sustaita
Deposited On:27 Mar 2017 22:19
Last Modified:03 Oct 2019 16:50

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