LAUSR

ntestinal iron absorption is a highly regulated physiIological process that determines overall body iron levels, because humans and other mammals cannot efficiently excrete excess iron. Dietary iron is absorbed mainly by duodenal enterocytes. Iron export by these cells is the rate-limiting step in assimilation of dietary iron, which involves ferrous iron export by ferroportin, followed by oxidation to the ferric state. Ferric iron then binds to the iron transport protein transferrin (TF) in the interstitial fluids of the villus lamina propria for distribution to the liver in the portal blood circulation. Iron oxidation is mediated by ferroxidase (FOX) proteins, including hephaestin (HEPH) and possibly ceruloplasmin (CP). The HEPH protein is embedded in the exofacial aspect of the basolateral membrane of duodenal enterocytes, whereas CP is found in serum, and a membrane-anchored form is expressed in various cell types (eg, hepatocytes, macrophages, astrocytes). Intestinal HEPH has been shown to be necessary for optimal intestinal iron transport in mice, but the influence of CP on this process has not been clarified. The current investigation by Fuqua et al in the current issue of Cellular and Molecular Gastroenterology and Hepatology provides novel insight into molecular mechanisms of intestinal iron absorption. The aim of this investigation was to further clarify the physiological roles of the multicopper ferroxidase (MCF) proteins, HEPH and CP, in intestinal iron transport. In this study, the authors tested the hypothesis that iron oxidation by CP complements the FOX activity of HEPH in the upper small intestine. The experimental approach was to cross mice lacking HEPH globally (Heph), or only in the intestinal epithelium (Heph), with global CP knockout (KO) (Cp) mice, thus generating double MCF KO mice. The rationale was that it might not be possible to directly assess CP function in the small intestine in the presence of HEPH because both proteins oxidize ferrous iron. The authors noted that global KO of both MCF-encoding genes (in HephCp mice) led to impaired post-natal growth, splenomegaly and cardiomegaly, iron loading in multiple tissues, depletion of serum iron, and severe hypochromic, microcytic anemia. Some of these physiological perturbations were likely a direct result of the severe anemia (eg, spleen and heart enlargement, impaired growth), whereas others specifically related to a lack of CP FOX activity (eg, iron loading in liver and some other tissues). Moreover, although no overt defect in intestinal iron transport was noted in the absence of these FOXs, evidence suggested that iron absorption in the double KO