title: Decreased hephaestin activity in the intestine of copper-deficient mice causes systemic iron deficiency.
abstract: Copper and iron metabolism intersect in mammals. Copper deficiency simultaneously leads to decreased iron levels in some tissues and iron deficiency anemia, whereas it results in iron overload in other tissues such as the intestine and liver. The copper requirement of the multicopper ferroxidases hephaestin and ceruloplasmin likely explains this link between copper and iron homeostasis in mammals. We investigated the effect of in vivo and in vitro copper deficiency on hephaestin (Heph) expression and activity. C57BL/6J mice were separated into 2 groups on the day of parturition. One group was fed a copper-deficient diet and another was fed a control diet for 6 wk. Copper-deficient mice had significantly lower hephaestin and ceruloplasmin (approximately 50% of controls) ferroxidase activity. Liver hepcidin expression was significantly downregulated by copper deficiency (approximately 60% of controls), and enterocyte mRNA and protein levels of ferroportin1 were increased to 2.5 and 10 times, respectively, relative to controls, by copper deficiency, indicating a systemic iron deficiency in the copper-deficient mice. Interestingly, hephaestin protein levels were significantly decreased to approximately 40% of control, suggesting that decreased enterocyte copper content leads to decreased hephaestin synthesis and/or stability. We also examined the effect of copper deficiency on hephaestin in vitro in the HT29 cell line and found dramatically decreased hephaestin synthesis and activity. Both in vivo and in vitro studies indicate that copper is required for the proper processing and/or stability of hephaestin.
authors.affiliation: Department of Nutritional Sciences and Toxicology, University of California, Berkeley, CA 94720-3104, USA.
authors.forename: Huijun
authors.initials: H
authors.lastname: Chen
authors.forename: Gang
authors.initials: G
authors.lastname: Huang
authors.forename: Trent
authors.initials: T
authors.lastname: Su
authors.forename: Hua
authors.initials: H
authors.lastname: Gao
authors.forename: Zouhair K
authors.initials: ZK
authors.lastname: Attieh
authors.forename: Andrew T
authors.initials: AT
authors.lastname: McKie
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Anderson
authors.forename: Chris D
authors.initials: CD
authors.lastname: Vulpe
mesh_terms: D018798:Anemia, Iron-Deficiency / Q000209:etiology*; D000818:Animals; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms; D003300:Copper / Q000172:deficiency*; D005260:Female; D006801:Humans; D008565:Membrane Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D011247:Pregnancy; D012016:Reference Values; D013482:Superoxide Dismutase / Q000378:metabolism
chemical_list: C117324:Heph protein, mouse; D008565:Membrane Proteins; D003300:Copper; D013482:Superoxide Dismutase