title: The multicopper ferroxidase hephaestin enhances intestinal iron absorption in mice.
abstract: Hephaestin is a vertebrate multicopper ferroxidase important for the transfer of dietary iron from intestinal cells to the blood. Hephaestin is mutated in the sex-linked anemia mouse, resulting in iron deficiency. However, sex-linked anemia mice still retain some hephaestin ferroxidase activity. They survive, breed, and their anemia improves with age. To gain a better understanding of the role of hephaestin in iron homeostasis, we used the Cre-lox system to generate knockout mouse models with whole body or intestine-specific (Villin promoter) ablation of hephaestin. Both types of mice were viable, indicating that hephaestin is not essential and that other mechanisms, multicopper ferroxidase-dependent or not, must compensate for hephaestin deficiency. The knockout strains, however, both developed a microcytic, hypochromic anemia, suggesting severe iron deficiency and confirming that hephaestin plays an important role in body iron acquisition. Consistent with this, the knockout mice accumulated iron in duodenal enterocytes and had reduced intestinal iron absorption. In addition, the similarities of the phenotypes of the whole body and intestine-specific hephaestin knockout mice clarify the important role of hephaestin specifically in intestinal enterocytes in maintaining whole body iron homeostasis. These mouse models will serve as valuable tools to study the role of hephaestin and associated proteins in iron transport in the small intestine and other tissues.
authors.affiliation: Department of Nutritional Science and Toxicology, University of California, Berkeley, Berkeley, California, United States of America; Iron Metabolism Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
authors.forename: Brie K
authors.initials: BK
authors.lastname: Fuqua
authors.affiliation: Iron Metabolism Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
authors.forename: Yan
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Iron Metabolism Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
authors.forename: Deepak
authors.initials: D
authors.lastname: Darshan
authors.affiliation: Iron Metabolism Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
authors.forename: David M
authors.initials: DM
authors.lastname: Frazer
authors.affiliation: Iron Metabolism Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Wilkins
authors.affiliation: FM Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Natalie
authors.initials: N
authors.lastname: Wolkow
authors.affiliation: Department of Nutritional Science and Toxicology, University of California, Berkeley, Berkeley, California, United States of America.
authors.forename: Austin G
authors.initials: AG
authors.lastname: Bell
authors.affiliation: Department of Nutritional Science and Toxicology, University of California, Berkeley, Berkeley, California, United States of America.
authors.forename: JoAnn
authors.initials: J
authors.lastname: Hsu
authors.affiliation: Department of Nutritional Science and Toxicology, University of California, Berkeley, Berkeley, California, United States of America.
authors.forename: Catherine C
authors.initials: CC
authors.lastname: Yu
authors.affiliation: Medical School, Nanjing University, Nanjing, Jiangsu Province, China.
authors.forename: Huijun
authors.initials: H
authors.lastname: Chen
authors.affiliation: FM Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Joshua L
authors.initials: JL
authors.lastname: Dunaief
authors.affiliation: Iron Metabolism Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia; School of Chemistry and Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia.
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Anderson
authors.affiliation: Department of Nutritional Science and Toxicology, University of California, Berkeley, Berkeley, California, United States of America.
authors.forename: Chris D
authors.initials: CD
authors.lastname: Vulpe
mesh_terms: D000818:Animals; D001835:Body Weight; D005260:Female; D005838:Genotype; D007408:Intestinal Absorption / Q000235:genetics; D007413:Intestinal Mucosa / Q000378:metabolism*; D007501:Iron / Q000378:metabolism*; D000090463:Iron Deficiencies; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010641:Phenotype
chemical_list: C117324:Heph protein, mouse; D008565:Membrane Proteins; D007501:Iron