Hephaestin, a ceruloplasmin homologue implicated in intestinal iron transport, is defective in the sla mouse

  title={Hephaestin, a ceruloplasmin homologue implicated in intestinal iron transport, is defective in the sla mouse},
  author={Chris D. Vulpe and Yien Ming Kuo and Therese L. Murphy and L. Cowley and Candice C. Askwith and Nataliya Libina and Jane Gitschier and Gregory J. Anderson},
  journal={Nature Genetics},
Iron is essential for many cellular functions; consequently, disturbances of iron homeostasis, leading to either iron deficiency or iron overload, can have significant clinical consequences. [] Key Result We describe here a novel gene, Heph, encoding a transmembrane–bound ceruloplasmin homologue that is mutant in the sla mouse and highly expressed in intestine. We suggest that the hephaestin protein is a multi–copper ferroxidase necessary for iron egress from intestinal enterocytes into the circulation and…

Systemic regulation of Hephaestin and Ireg1 revealed in studies of genetic and nutritional iron deficiency.

Iron levels and expression of genes involved in iron uptake and storage in sla mice and C57BL/6J mice fed iron-deficient, iron-overload, or control diets are compared to indicate that Dmt1 can be modulated by the enterocyte iron level, whereas Hephaestin and Ireg1 expression respond to systemic rather than local signals of iron status.

The Multicopper Ferroxidase Hephaestin Enhances Intestinal Iron Absorption in Mice

The knockout strains developed a microcytic, hypochromic anemia, suggesting severe iron deficiency and confirming that hephaestin plays an important role in body iron acquisition, and the similarities of the phenotypes of the whole body and intestine-specific hephalestin knockout mice clarify the important role of hephaESTin specifically in intestinal enterocytes in maintaining whole body iron homeostasis.

Hepcidin: A putative iron-regulatory hormone relevant to hereditary hemochromatosis and the anemia of chronic disease

  • R. FlemingW. Sly
  • Medicine, Biology
    Proceedings of the National Academy of Sciences of the United States of America
  • 2001
The paper by Nicolas et al. in this issue of PNAS presents the exciting possibility that a central player in the communication of body iron stores to the intestinal absorptive cells may have been identified, the hepatic protein hepcidin.

The ceruloplasmin homolog hephaestin and the control of intestinal iron absorption.

Analysis of the sla mouse has supported the model for the regulation of intestinal iron absorption whereby changes in systemic iron requirements alter the levels of basolateral transport components with subsequent regulation of brush border transport.

Intestinal hephaestin potentiates iron absorption in weanling, adult, and pregnant mice under physiological conditions.

Results demonstrate that intestinal Heph is essential for optimal iron transport in weanlings and adults of both sexes and during pregnancy, but not in adult mice with iron-deficiency or hemolytic anemia.

Studies on the roles of human ferroportin and hephaestin in iron homeostasis

It is suggested that Fpn1 is the major, if not the sole, exporter protein for iron and hephaestin (Hpn), a multicopper ferroxidase in the basolateral membrane of duodenal enterocytes, is intimately involved in iron export from enterocytes into the blood.

Targeted gene disruption reveals an essential role for ceruloplasmin in cellular iron efflux.

An essential physiologic role for ceruloplasmin is revealed in determining the rate of iron efflux from cells with mobilizable iron stores, suggesting that iron accumulation results from altered compartmentalization within the iron cycle.

Physiology of iron transport and the hemochromatosis gene.

  • A. Pietrangelo
  • Biology
    American journal of physiology. Gastrointestinal and liver physiology
  • 2002
A model of HFE function in iron metabolism is presented, which is homologous to major histocompatibility complex class I proteins but is not an iron carrier, whereas biochemical and cell biological studies have shown that the transferrin receptor, the main protein devoted to cellular uptake of transferrin iron, interacts with HFE.

Hephaestin is a ferroxidase that maintains partial activity in sex-linked anemia mice.

It is suggested that hephaestin, by way of its ferroxidase activity, facilitates iron export from intestinal enterocytes, most likely in cooperation with the basolateral iron transporter, Ireg1.



Genetic defects of iron transport.

Five genetic traits in man and laboratory animals have major effects on iron transport and their phenotypic interaction with nutritional factors, especially the form and quantity of iron in the diet, may provide new insights for the study of nutrition.

Regulation of intestinal non-haem iron absorption.

Evidence is drawn together from older physiological experiments and more recent studies using cell and molecular biology techniques to speculate how this recent information may be pertinent to how iron is taken up by enterocytes, how its transfer to plasma is controlled and, finally, how information about body iron stores or requirement is conveyed to enterocytes.

Iron metabolism in copper-deficient swine.

The observed abnormalities in iron metabolism are best explained by an impaired ability of the duodenal mucosa, the reticuloendothelial system, and the hepatic parenchymal cell to release iron to the plasma.

Hereditary hemochromatosis: etiologic, pathologic, and clinical aspects.

Using this approach it is now possible to detect individuals homozygous or heterozygous for the HFE gene using a simple polymerase chain reaction-based test, which promises to provide fresh insights into the range of phenotypic expression in hereditary hemochromatosis.

Ferritin distribution and synthesis in sex-linked anemia.

Results indicating a high level of duodenal ferritin synthesis in standard-fed mice with sex-linked anemia suggest that the primary genetic defect is more likely a disorder of intramucosal iron transport than a primary disturbance of ferritIn metabolism.

Ceruloplasmin gene expression in the murine central nervous system.

Aceruloplasminemia is an autosomal recessive disorder resulting in neurodegeneration of the retina and basal ganglia in association with iron accumulation in these tissues. To begin to define the

Hereditary deficiency of ferroxidase (aka caeruloplasmin)

  • J. I. Logan
  • Biology
    Journal of neurology, neurosurgery, and psychiatry
  • 1996
Caeruloplasmin catalysed oxidation of the exported ferrous iron is still required because spontaneous ferrous oxidation cannot provide a sufficiently large supply of ferric iron for binding to transferrin and subsequent distribution to the body.

Active Transport of Iron by Intestine: Selective Genetic Defect in the Mouse

These studies on everted gut sacs in vitro provide the first direct evidence of a selective genetic defect in the second or serosal transfer step of the active transport mechanism for iron in the duodenum of the sex-linked anaemic (sla) mouse.

The FET3 Gene Product Required for High Affinity Iron Transport in Yeast Is a Cell Surface Ferroxidase (*)

Cells that contain a functional FET3 gene product exhibited an iron-dependent non-mitochondrial increase in oxygen consumption and comparison of the rate of iron oxidation to O2 consumption yielded an approximate value of 4:1, as predicted for a ferroxidase.

Molecular biology of iron acquisition in Saccharomyces cerevisiae

The mechanism by which these genes act in concert to ensure iron accumulation in S. cerevisiae presents an intriguing picture, drawing parallels with observations made in the human system almost 40 years ago.