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

Autor:	Fuqua BK; Department of Nutritional Science and Toxicology, University of California, Berkeley, Berkeley, California.; Iron Metabolism Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia., Lu Y; Iron Metabolism Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia., Frazer DM; Iron Metabolism Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia., Darshan D; Iron Metabolism Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia., Wilkins SJ; Iron Metabolism Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia., Dunn L; Iron Metabolism Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia., Loguinov AV; Department of Nutritional Science and Toxicology, University of California, Berkeley, Berkeley, California., Kogan SC; Department of Laboratory Medicine and Helen Diller Comprehensive Cancer Center and Mouse Pathology Core, University of California, San Francisco, California., Matak P; Department of Pharmacology and Cancer Biology, Duke University, Duke University Medical Center, Durham, North Carolina., Chen H; Medical School, Nanjing University, Nanjing, Jiangsu Province, China., Dunaief JL; FM Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, University of Pennsylvania, Philadelphia, Pennsylvania., Vulpe CD; Department of Nutritional Science and Toxicology, University of California, Berkeley, Berkeley, California., Anderson GJ; Iron Metabolism Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.; School of Chemistry and Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia.
Jazyk:	angličtina
Zdroj:	Cellular and molecular gastroenterology and hepatology [Cell Mol Gastroenterol Hepatol] 2018 Jun 23; Vol. 6 (4), pp. 405-427. Date of Electronic Publication: 2018 Jun 23 (Print Publication: 2018).
DOI:	10.1016/j.jcmgh.2018.06.006
Abstrakt:	Background & Aims: Multicopper ferroxidases (MCFs) facilitate intestinal iron absorption and systemic iron recycling, likely by a mechanism involving the oxidization of Fe 2+ from the iron exporter ferroportin 1 for delivery to the circulating Fe 3+ 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 ( Heph int/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 ( Heph int/int Cp -/- ) 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. Heph int/int Cp -/- mice were moderately anemic (similar to Cp -/- mice) but were iron loaded only in the duodenum and liver, as in Heph int/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.
Databáze:	MEDLINE
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