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.
Highlights
Every day, billions of iron atoms from the diet must be transferred from intestinal cells to the blood in order to maintain iron balance
The transfer of iron across biological membranes is usually associated with the oxidation or reduction of the iron, and current evidence supports an important role for the vertebrate multicopper ferroxidase (MCF) hephaestin (HEPH) in the export of iron from intestinal enterocytes [1]
The targeted exon in Heph was undetectable in the Heph-/y enterocytes but downstream exons were still present in Heph-/y enterocytes at levels approximately half that of WT controls
Summary
Billions of iron atoms from the diet must be transferred from intestinal cells to the blood in order to maintain iron balance. HEPH is hypothesized to oxidize ferrous iron from the only known intestinal iron exporter, ferroportin (FPN1), a multi-pass membrane protein that has been demonstrated in other cell types to require a ferroxidase to function [2,3,4]. This catalyzed oxidation step ensures that adequate iron is available to bind to its carrier in the blood, transferrin, which, under physiological conditions, only binds ferric iron [5,6]. Unlike CP, no HEPH expression has been detected in the liver or serum [1,9]
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