Severe Iron Metabolism Defects in Mice With Double Knockout of the Multicopper Ferroxidases Hephaestin and Ceruloplasmin

Lu, Yan ; Anderson, Gregory J. ; et al.

In: Cellular and Molecular Gastroenterology and Hepatology Cellular and Molecular Gastroenterology and Hepatology, Jg. 6 (2018), Heft 4, S. 405-427

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Background & Aims Multicopper ferroxidases (MCFs) facilitate intestinal iron absorption and systemic iron recycling, likely by a mechanism involving the oxidization of Fe2+ from the iron exporter ferroportin 1 for delivery to the circulating Fe3+ carrier transferrin. Hephaestin (HEPH), the only MCF known to be expressed in enterocytes, aids in the basolateral transfer of dietary iron to the blood. Mice lacking HEPH in the whole body (Heph-/-) or intestine alone (Hephint/int) exhibit defects in dietary iron absorption but still survive and grow. Circulating ceruloplasmin (CP) is the only other known MCF likely to interact with enterocytes. Our aim was to assess the effects of combined deletion of HEPH and CP on intestinal iron absorption and homeostasis in mice. Methods Mice lacking both HEPH and CP (Heph-/-Cp-/-) and mice with whole-body knockout of CP and intestine-specific deletion of HEPH (Hephint/intCp-/-) were generated and phenotyped. Results Heph-/-Cp-/- mice were severely anemic and had low serum iron, but they exhibited marked iron loading in duodenal enterocytes, the liver, heart, pancreas, and other tissues. Hephint/intCp-/- mice were moderately anemic (similar to Cp-/- mice) but were iron loaded only in the duodenum and liver, as in Hephint/int and Cp-/- mice, respectively. Both double knockout models absorbed iron in radiolabeled intestinal iron absorption studies, but the iron was inappropriately distributed, with an abnormally high percentage retained in the liver. Conclusions These studies indicate that HEPH and CP, and likely MCFs in general, are not essential for intestinal iron absorption but are required for proper systemic iron distribution. They also point to important extra-intestinal roles for HEPH in maintaining whole-body iron homeostasis.

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Titel:	Severe Iron Metabolism Defects in Mice With Double Knockout of the Multicopper Ferroxidases Hephaestin and Ceruloplasmin
Autor/in / Beteiligte Person:	Lu, Yan ; Anderson, Gregory J. ; Matak, Pavle ; Chen, Huijun ; Wilkins, Sarah J. ; Kogan, Scott C. ; Darshan, Deepak ; Fuqua, Brie K. ; Loguinov, Alex ; Vulpe, Chris D. ; Dunn, Linda A. ; Dunaief, Joshua L. ; Frazer, David M.
Link:	View record in OpenAIRE (Volltext) https://pubmed.ncbi.nlm.nih.gov/30364771
Zeitschrift:	Cellular and Molecular Gastroenterology and Hepatology Cellular and Molecular Gastroenterology and Hepatology, Jg. 6 (2018), Heft 4, S. 405-427
Veröffentlichung:	2018
Medientyp:	unknown
ISSN:	2352-345X (print)
Schlagwort:	mice lacking CP in the whole body Male Hephaestin Hephfl/flCp polymerase chain reaction 3′-diaminobenzidine Mice 0302 clinical medicine PCR, polymerase chain reaction Homeostasis PBS Original Research Hephsla/slaCp-/-, mice lacking CP in the whole body and expressing only the sla mutant form of HEPH chemistry.chemical_classification HCI TBST Cp-/-, mice lacking CP in the whole body WT HEPH, hephaestin Gastroenterology HCI, hydrochloric acid GI, gastrointestinal GI 3. Good health Absorption, Physiological mice lacking CP in the whole body and expressing only the sla mutant form of HEPH PCR Editorial Organ Specificity mice lacking HEPH in the intestine alone Hephint/intCp-/-, mice lacking HEPH in the intestine alone and lacking CP in the whole body standard deviation Iron Overload Intestinal Iron Absorption FDR, false discovery rate Anemia Duodenum Knockout Physiological TIBC 03 medical and health sciences Hephfl/flCp-/-, mice with floxed Heph alleles and lacking CP in the whole body Hephsla/slaCp Hephint/int, mice lacking HEPH in the intestine alone total iron binding capacity mice with floxed Heph alleles Iron Deficiency Anemia Ligation Tris-buffered saline with 0.1% Tween-20 SD NTBI TBST, Tris-buffered saline with 0.1% Tween-20 Animal Cp MCF, multicopper ferroxidase mice with floxed Heph alleles and lacking CP in the whole body medicine.disease gastrointestinal WT, wild-type TF, transferrin Mice, Inbred C57BL 030104 developmental biology Enterocytes chemistry Iron-deficiency anemia CP, ceruloplasmin NTBI, non-transferrin bound iron Ceruloplasmin mice lacking HEPH in the intestine alone and lacking CP in the whole body 030217 neurology & neurosurgery Non-Transferrin Bound Iron 0301 basic medicine hydrochloric acid Inbred C57BL HEPH double-knockout mice lacking both HEPH and CP Heph-/-, mice lacking HEPH in the whole body Body Size sla Cation Transport Proteins Mice, Knockout multicopper ferroxidase biology medicine.diagnostic_test Heph-/-Cp-/- or DKO, double-knockout mice lacking both HEPH and CP Heph Animals, Suckling Phenotype CP Serum iron Female FPN1, ferroportin 1 Oxidation-Reduction TF sex-linked anemia hephaestin FPN1 Hephint/intCp Iron PBS, phosphate-buffered saline phosphate-buffered saline sla, sex-linked anemia Absorption FDR non-transferrin bound iron medicine DAB Animals transferrin mice lacking HEPH in the whole body Suckling Hephfl/fl lcsh:RC799-869 wild-type MCF Hepatology DAB, 3,3′-diaminobenzidine TIBC, total iron binding capacity Body Weight Membrane Proteins Metabolism ferroportin 1 Molecular biology Disease Models, Animal Transferrin Disease Models biology.protein Hephint/int lcsh:Diseases of the digestive system. Gastroenterology false discovery rate Heph-/-Cp-/- or DKO Hephfl/fl, mice with floxed Heph alleles SD, standard deviation
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