The Multicopper Ferroxidase Hephaestin Enhances Intestinal Iron Absorption in Mice

被引:72
作者
Fuqua, Brie K. [1 ,2 ]
Lu, Yan [2 ]
Darshan, Deepak [2 ]
Frazer, David M. [2 ]
Wilkins, Sarah J. [2 ]
Wolkow, Natalie [3 ]
Bell, Austin G. [1 ]
Hsu, JoAnn [1 ]
Yu, Catherine C. [1 ]
Chen, Huijun [4 ]
Dunaief, Joshua L. [3 ]
Anderson, Gregory J. [2 ,5 ]
Vulpe, Chris D. [1 ]
机构
[1] Univ Calif Berkeley, Dept Nutr Sci & Toxicol, Berkeley, CA 94720 USA
[2] QIMR Berghofer Med Res Inst, Iron Metab Lab, Brisbane, Qld, Australia
[3] Univ Penn, Scheie Eye Inst, FM Kirby Ctr Mol Ophthalmol, Philadelphia, PA 19104 USA
[4] Nanjing Univ, Sch Med, Nanjing 210008, Jiangsu, Peoples R China
[5] Univ Queensland, Sch Chem & Mol Biosci, Brisbane, Qld, Australia
基金
英国医学研究理事会; 澳大利亚研究理事会; 美国国家卫生研究院; 美国国家科学基金会;
关键词
LINKED ANEMIA; CERULOPLASMIN; CELLS; EXPRESSION; TRANSPORT; ANAEMIA; EFFLUX; MOUSE; GENE; FERROPORTIN;
D O I
10.1371/journal.pone.0098792
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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.
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页数:13
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