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Nutrient Physiology, Metabolism, and Nutrient-Nutrient Interactions

Decreased Hephaestin Activity in the Intestine of Copper-Deficient Mice Causes Systemic Iron Deficiency¹

Huijun Chen^*, Gang Huang^*, Trent Su^*, Hua Gao^*, Zouhair K. Attieh^*,, Andrew T. McKie^**, Gregory J. Anderson and Chris D. Vulpe^*,2

^* Department of Nutritional Sciences and Toxicology, University of California, Berkeley, CA 94720-3104; Biochemistry Department, School of Medicine, American University, Beirut, Lebanon; ^** Department of Molecular Medicine, King's College, London SE59NU, UK; and The Queensland Institute of Medical Research and the University of Queensland, Post Office Royal Brisbane Hospital, Brisbane, Queensland 4029, Australia

² To whom correspondence should be addressed. E-mail: vulpe{at}berkeley.edu.

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 (50% of controls) ferroxidase activity. Liver hepcidin expression was significantly downregulated by copper deficiency (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 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.

KEY WORDS: • copper • iron • hephaestin • ceruloplasmin • ferroportin1

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