Regulation of iron absorption in Hfe mutant mice

Ajioka, Richard S.; Levy, Joanne E.; Andrews, Nancy C.; Kushner, James P.

doi:10.1182/blood-2001-11-0037

Cited by 81 publications

(69 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Inadequate levels of hepcidin lead to excessive dietary iron absorption (80), excessive mobilization of macrophage iron stores (81), saturation of transferrin with iron, and the appearance of NTBI in plasma (82). Iron overload is also seen in ␤-thalassemia, a genetic disorder resulting from defective ␤-globin synthesis.…”

Section: Pathological Tissue Iron Overloadmentioning

confidence: 99%

Iron homeostasis: An anthropocentric perspective

Coffey

Ganz

2017

Journal of Biological Chemistry

158

159

View full text Add to dashboard Cite

The regulation of iron metabolism in biological systems centers on providing adequate iron for cellular function while limiting iron toxicity. Because mammals cannot excrete iron, mechanisms have evolved to control iron acquisition, storage, and distribution at both systemic and cellular levels. Hepcidin, the master regulator of iron homeostasis, controls iron flows into plasma through inhibition of the only known mammalian cellular iron exporter ferroportin. Hepcidin is feedback-regulated by iron status and strongly modulated by inflammation and erythropoietic demand. This review highlights recent advances that have changed our understanding of iron metabolism and its regulation.

show abstract

Section: Pathological Tissue Iron Overloadmentioning

confidence: 99%

Iron homeostasis: An anthropocentric perspective

Coffey

Ganz

2017

Journal of Biological Chemistry

158

159

View full text Add to dashboard Cite

show abstract

“…5 HFE requires ␤2-microglobulin (␤2m) for appropriate cell surface expression, 6 and in fact both Hfe Ϫ/Ϫ and ␤2m Ϫ/Ϫ mice recapitulate human HH and develop iron overload in the liver because of iron hyperabsorption in the duodenum. [7][8][9] HFE influences iron homeostasis through its binding to transferrin receptor 1 (TfR1), which is part of the major cellular iron uptake pathway, and by reducing the affinity of TfR1 for transferrin (Tf), thus competing with Tf binding.…”

mentioning

confidence: 99%

Repression of Repulsive Guidance Molecule C during Inflammation Is Independent of Hfe and Involves Tumor Necrosis Factor-α

Constante

Wang

Raymond

et al. 2007

The American Journal of Pathology

View full text Add to dashboard Cite

Genetic iron overload, or hemochromatosis, can be caused by mutations in HFE, hemojuvelin, and hepcidin genes. Hepcidin, a negative regulator of intestinal iron absorption, is found to be inappropriately low in both patients and in animal models, indicating that proper control of basal hepcidin levels requires both hemojuvelin and HFE. In mice, repulsive guidance molecule c (Rgmc, the hemojuvelin mouse ortholog) and hepcidin levels are transcriptionally regulated during inflammation. Here, we report that basal Rgmc levels in Hfe-deficient mice are normal and that these mice retain the ability to suppress Rgmc expression after lipopolysaccharide (LPS) challenge. Thus, Rgmc regulation by LPS is Hfe-independent. The response of Rgmc to LPS involves signaling through toll-like receptor 4 (Tlr4), because Tlr4-deficient mice do not show altered Rgmc expression after LPS administration. We further show that tumor necrosis factor-␣, but not interleukin-6, is sufficient to cause Rgmc down-regulation by LPS. These results contrast with previous data demonstrating that hepcidin levels are directly regulated by interleukin-6 but not by tumor necrosis factor-␣. The regulation of iron-related genes by different cytokines may allow for time-dependent control of iron metabolism changes during inflammation and may be relevant to chronic inflammation, infections, and cancer settings, leading to the development of anemia of chronic disease.

show abstract

“…48 These observations indicate that hepcidin regulation by iron may rely on cross-communication between hepatocytes and RE macrophages in an Hfe-dependent fashion. Moreover, the fact that HH patients and animal models retain the capacity to appropriately regulate iron absorption in response to variations in iron status and erythroid demand 49,50 suggests that Hfe deficiency leads to quantitative rather than qualitative changes in hepcidin expression.Our experiments, in which Hfe Ϫ/Ϫ mice were reconstituted with Hfe-expressing macrophages (wt 3 Hfe Ϫ/Ϫ ), show that restoring Hfe expression in RE cells can significantly inhibit iron loading. In fact, wt 3 Hfe Ϫ/Ϫ mice had hepatic iron levels that were approximately one third lower than those in Hfe Ϫ/Ϫ 3 Hfe Ϫ/Ϫ mice.…”

mentioning

confidence: 99%

Contribution of Hfe expression in macrophages to the regulation of hepatic hepcidin levels and iron loading

Makui

Soares

Jiang

et al. 2005

Blood

View full text Add to dashboard Cite

Hereditary hemochromatosis (HH), an iron overload disease associated with mutations in the HFE gene, is characterized by increased intestinal iron absorption and consequent deposition of excess iron, primarily in the liver. Patients with HH and Hfe-deficient (Hfe ؊/؊ ) mice manifest inappropriate expression of the iron absorption regulator hepcidin, a peptide hormone produced by the liver in response to iron loading. In this study, we investigated the contribution of Hfe expression in macrophages to the regulation of liver hepcidin levels and iron loading. We used bone marrow transplantation to generate wild-type (wt) and Hfe ؊/؊ mice chimeric for macrophage Hfe gene expression. Reconstitution of Hfe-deficient mice with wt bone marrow resulted in augmented capacity of the spleen to store iron and in significantly decreased liver iron loading, accompanied by a significant increase of hepatic hepcidin mRNA levels. Conversely, wt mice reconstituted with Hfedeficient bone marrow had a diminished capacity to store iron in the spleen but no significant alterations of liver iron stores or hepcidin mRNA levels. Our results suggest that macrophage Hfe participates in the regulation of splenic and liver iron concentrations and liver hepcidin expression. ( IntroductionHereditary hemochromatosis (HH) type 1, an autosomal recessive disease of iron overload, is one of the most common inherited disorders. It is characterized by failure in the regulation of duodenal iron absorption, leading to iron overloading that can eventually impair organ systems and cause cirrhosis, diabetes, and cardiomyopathy. 1 HH is caused by mutations in the HFE gene encoding a major histocompatibility complex (MHC) class 1-like protein that requires ␤2-microglobulin (B2m) for cell surface expression. 2 A link between HFE and cellular iron metabolism is suggested by the observation that wild-type (wt) HFE-␤ 2 m molecules form a stable complex with transferrin receptor 1 (TfR1). 3 Most patients with HH are homozygous for a missense mutation in the HFE gene that results in cysteine-to-tyrosine substitution at amino acid 282 of HFE protein (C282Y). 2 The mutation disrupts a critical disulfide bond in the ␣ 3 domain of HFE protein and abrogates binding of the mutant HFE protein to B2m, leading to impaired HFE protein intracellular trafficking, incorporation into the cell membrane, and association with TfR1. 3 Studies in mice with targeted inactivation of the Hfe or B2m gene have confirmed the critical role of HFE-B2m complexes in iron metabolism. [4][5][6] As do humans with HH, Hfe-deficient mice develop iron overloading with an accumulation of excess iron, primarily in liver parenchymal cells, as opposed to reticuloendothelial (RE) cell storage characteristic of secondary iron overload. Thus, abnormal regulation of iron metabolism in RE cells seems to take place in HH because these cells are relatively iron deficient compared with surrounding parenchymal hepatocytes. 7 Importantly, RE cells-monocytes and tissue macrophages-have a central role in regulat...

show abstract

Regulation of iron absorption in Hfe mutant mice

Cited by 81 publications

References 30 publications

Iron homeostasis: An anthropocentric perspective

Iron homeostasis: An anthropocentric perspective

Repression of Repulsive Guidance Molecule C during Inflammation Is Independent of Hfe and Involves Tumor Necrosis Factor-α

Contribution of Hfe expression in macrophages to the regulation of hepatic hepcidin levels and iron loading

Contact Info

Product

Resources

About