Physiologic systemic iron metabolism in mice deficient for duodenal Hfe. Blood

Molecular Medicine Partnership Unit, University of Heidelberg, Germany.
Blood (Impact Factor: 10.45). 06/2007; 109(10):4511-7. DOI: 10.1182/blood-2006-07-036186
Source: PubMed


Mutations in the Hfe gene result in hereditary hemochromatosis (HH), a disorder characterized by increased duodenal iron absorption and tissue iron overload. Identification of a direct interaction between Hfe and transferrin receptor 1 in duodenal cells led to the hypothesis that the lack of functional Hfe in the duodenum affects TfR1-mediated serosal uptake of iron and misprogramming of the iron absorptive cells. Contrasting this view, Hfe deficiency causes inappropriately low expression of the hepatic iron hormone hepcidin, which causes increased duodenal iron absorption. We specifically ablated Hfe expression in mouse enterocytes using Cre/LoxP technology. Mice with efficient deletion of Hfe in crypt- and villi-enterocytes maintain physiologic iron metabolism with wild-type unsaturated iron binding capacity, hepatic iron levels, and hepcidin mRNA expression. Furthermore, the expression of genes encoding the major intestinal iron transporters is unchanged in duodenal Hfe-deficient mice. Our data demonstrate that intestinal Hfe is dispensable for the physiologic control of systemic iron homeostasis under steady state conditions. These findings exclude a primary role for duodenal Hfe in the pathogenesis of HH and support the model according to which Hfe is required for appropriate expression of the "iron hormone" hepcidin which then controls intestinal iron absorption.

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Available from: Judit Kiss, Jan 27, 2014
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    • "Floxed DNA was, however, also detected in the Hephint/y enterocytes. This may be explained by either contamination from other intestinal cell types or by incomplete recombination, as has been reported previously in other intestinal knockout mice generated with this particular Cre transgene [31]. By immunoblot, most Hephint/y mice had little to no detectable HEPH protein expression in isolated enterocytes (Figure S2). "
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    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.
    PLoS ONE 06/2014; 9(6):e98792. DOI:10.1371/journal.pone.0098792 · 3.23 Impact Factor
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    • "The answer to whether Hfe alters cellular iron uptake by serving as a sensor mechanism in duodenal enterocytes was provided through the generation of mice bearing a selective deficiency of Hfe in the duodenal enterocytes (Vujic Spasic et al., 2007). Surprisingly, mice lacking Hfe in intestinal cells showed no iron accumulation in the liver nor hepatic hepcidin deficiency overruling the traditional hypothesis that duodenal Hfe played a gatekeeper role in controlling systemic iron homeostasis (Vujic Spasic et al., 2007). The question where Hfe acts to control iron homeostasis was revealed through the generation of mice with selective deficiency of Hfe in hepatocytes which recapitulated most of the anomalies within iron metabolism observed in constitutive Hfe mutant mice and HFE-HH patients (Adams, 2003; Wigg et al., 2003; Vujic Spasic et al., 2008; Adams and Barton, 2010). "
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    ABSTRACT: Iron-overload disorders owing to genetic misregulation of iron acquisition are referred to as hereditary hemochromatosis (HH). The most prevalent genetic iron overload disorder in Caucasians is caused by mutations in the HFE gene, an atypical MHC class I molecule. Recent studies classified HFE/Hfe-HH as a liver disease with the primarily failure in the production of the liver iron hormone hepcidin in hepatocytes. Inadequate hepcidin expression signals for excessive iron absorption from the diet and iron deposition in tissues causing multiple organ damage and failure. This review focuses on the molecular actions of the HFE/Hfe and hepcidin in maintaining systemic iron homeostasis and approaches undertaken so far to combat iron overload in HFE/Hfe-HH. In the light of the recent investigations, novel roles of extra-hepatocytic Hfe are discussed raising a question to the relevance of the multipurpose functions of Hfe for the understanding of HH-associated pathologies.
    Frontiers in Pharmacology 03/2014; 5:42. DOI:10.3389/fphar.2014.00042 · 3.80 Impact Factor
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    • "The most common mutation in HFE is a single nucleotide change resulting in a C to Y substitution at amino acid 282. Recent studies have clarified the crucial role of HFE as a hepatocyte iron sensor and upstream regulator of hepcidin [99, 100], and several mechanisms by which this protein may regulate iron metabolism have been proposed. It may compete with transferrin for binding to TfR1, thus lowering iron uptake into cells [101, 102]. "
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    ABSTRACT: Molecular iron metabolism and its regulation are least well understood in the fetal and early postnatal periods of mammalian ontogenic development. The scope of this review is to summarize recent progress in uncovering the molecular mechanisms of fetal iron homeostasis, introduce the molecules involved in iron transfer across the placenta, and briefly explain the role of iron transporters in the absorption of this microelement during early postnatal life. These issues are discussed and parallels are drawn with the relatively well-established system for elemental and heme iron regulation in adult mammals. We conclude that detailed investigations into the regulatory mechanisms of iron metabolism at early stages of development are required in order to optimize strategies to prevent neonatal iron deficiency. We propose that newborn piglets represent a suitable animal model for studies on iron deficiency anemia in neonates.
    Cellular and Molecular Life Sciences CMLS 05/2012; 70(1). DOI:10.1007/s00018-012-1018-1 · 5.81 Impact Factor
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