Structure and liver cell expression pattern of the HFE gene in the rat

Holmström, Petra; Dzikaite, Vijole; Hultcrantz, Rolf; Melefors, Öjar; Eckes, Kristina; Stål, Per; Kinnman, Nils; Smedsrød, Bård; Gåfvels, Mats; Eggertsen, Gösta

doi:10.1016/s0168-8278(03)00293-9

Cited by 25 publications

(20 citation statements)

References 31 publications

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“…Hfe is predominantly expressed in the liver, with the highest levels of Hfe mRNA found in hepatocytes. 22,23 This is consistent with the finding that Hfe deletion primarily affects the liver. Presumably other ␤2m-dependent molecules might be more relevant in the heart and pancreas, which also express hepcidin.…”

Section: Resultssupporting

confidence: 91%

Contributions of β2-microglobulin–dependent molecules and lymphocytes to iron regulation: insights from HfeRag1-/- and β2mRag1-/- double knock-out mice

Miranda

Makui

Andrews

et al. 2004

Blood

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Genetic causes of hereditary hemochromatosis (HH) include mutations in the HFE gene, coding for a ␤2-microglobulin (␤2m)-associated major histocompatibility complex class I-like protein. However, iron accumulation in patients with HH can be highly variable. Previously, analysis of ␤2mRag1 ؊/؊ double-deficient mice, lacking all ␤2m-dependent molecules and lymphocytes, demonstrated increased iron accumulation in the pancreas and heart compared with ␤2m single knock-out mice. To evaluate whether the observed phenotype in ␤2mRag1 ؊/؊ mice was due solely to the absence of Hfe or to other ␤2m-dependent molecules, we generated HfeRag1 ؊/؊ double-deficient mice. Our studies revealed that introduction of Rag1 deficiency in Hfe knock-out mice leads to heightened iron overload, mainly in the liver, whereas the heart and pancreas are relatively spared compared with IntroductionThe protein involved in hereditary hemochromatosis (HH), HFE, has been identified as a ␤2-microglobulin (␤2m)-dependent, major histocompatibility complex class I (MHC-I)-like molecule, 1 complementing earlier findings that ␤2m deficiency in mice leads to iron overload. 2 Significantly, knock-out of the Hfe gene clearly confers the HH phenotype to mice. 3,4 Although HFE mutations are clearly associated with iron overload, the marked variability of the phenotype among homozygous individuals for the same HFE mutations indicates that other environmental and genetic factors modify disease severity. 5 Earlier reports show that defective numbers of peripheral lymphocytes and liver lymphocyte populations are associated with a more severe clinical expression of iron overload and damage in HH. 6,7 Previously, we investigated the effect of total lymphocyte absence in iron overload by crossing ␤2m Ϫ/Ϫ mice, lacking all ␤2m-dependent MHC-I molecules, 2 with mice deficient in recombinase activator gene 1 (Rag1) required for normal B-and T-lymphocyte development. 8 Immunodeficient ␤2mRag1 Ϫ/Ϫ mice develop iron overload and, unlike their single knock-out counterparts, when challenged with dietary iron loading, iron accumulation occurs not only in the liver but also massively in the pancreas and heart myocytes. 9 In this report, we further investigate the possible involvement of ␤2m-dependent molecules and lymphocytes in iron regulation. We examine changes in iron metabolism in compound mutant HfeRag Ϫ/Ϫ and ␤2mRag1 Ϫ/Ϫ mice placed on a standard diet and after dietary iron challenge. Study designAll procedures were performed in accordance with guidelines of Canadian Council on Animal Care and approved by the Animal Care Committee of the Centre Hospitalier de l'Université de Montréal. Hfe Ϫ/Ϫ mice have been described previously. 3 ␤2m Ϫ/Ϫ and Rag1 Ϫ/Ϫ mice were purchased from Jackson Laboratories (Bar Harbor, ME). All mutant mice have been back-crossed a minimum of 5 times onto the C57BL/6 (B6) background. Compound mutants ␤2mRag1 Ϫ/Ϫ and HfeRag1 Ϫ/Ϫ were obtained as described. 9 Mouse peripheral blood cells were screened by flow cytometry in a Coulter Epics Elite cou...

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Section: Resultssupporting

confidence: 91%

Contributions of β2-microglobulin–dependent molecules and lymphocytes to iron regulation: insights from HfeRag1-/- and β2mRag1-/- double knock-out mice

Miranda

Makui

Andrews

et al. 2004

Blood

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“…Both cell types normally express HFE. 40,41 Since HFE can result in either the accumulation or depletion of intracellular iron stores, we speculate that it can interact with either the proteins involved in the import or export of iron and that the differences seen between cell lines and in tissues depends on the ratios of exporters and importers and TfR1. HFE appears to cause accumulation of intracellular iron in cell lines that exhibit active iron efflux.…”

Section: Discussionmentioning

confidence: 99%

The hereditary hemochromatosis protein, HFE, lowers intracellular iron levels independently of transferrin receptor 1 in TRVb cells

Carlson

Zhang

Fleming

et al. 2005

Blood

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Hereditary hemochromatosis (HH) is an autosomal recessive disease that leads to parenchymal iron accumulation. The most common form of HH is caused by a single amino acid substitution in the HH protein, HFE, but the mechanism by which HFE regulates iron homeostasis is not known. In the absence of transferrin (Tf), HFE interacts with transferrin receptor 1 (TfR1) and the 2 proteins co-internalize, and in vitro studies have shown that HFE and Tf compete for TfR1 binding. IntroductionHereditary hemochromatosis (HH) is a common autosomal recessive disease of iron metabolism characterized by gradual accumulation of excess iron in organs such as the liver, heart, pancreas, and thyroid, resulting in symptoms, including hepatic cirrhosis and hepatocellular carcinoma, cardiomyopathy and arrhythmias, diabetes, and hypogonadotropic hypogonadism. 1,2 The most common form of HH is caused by a single base pair mutation in the HH gene that results in the substitution of tyrosine for cysteine at amino acid position 260 (C260Y; The numbering system for both HFE and low-density lipoprotein receptor [LDLR] is based on the mature protein and does not include the signal sequence) in the mature protein, HFE. 3 HFE is an atypical major histocompatibility complex (MHC) class 1-related protein. The C260Y mutation disrupts a disulfide bond in its ␣3 domain, which abrogates its association with the ␤2-microglobulin (␤2M) light chain and subsequent trafficking to the cell surface. 4 Although the importance of functional HFE-␤2M heterodimers in the maintenance of iron homeostasis has been further documented in studies using HFE knock-out mice, 5,6 the mechanism by which HFE regulates iron metabolism in cells is still unknown.In vitro and in vivo studies show that HFE associates with transferrin receptor 1 (TfR1) at neutral pH [7][8][9][10] and that the binding sites for HFE and Tf overlap in TfR. [11][12][13] In vitro experiments demonstrate that HFE competes with Tf for binding to TfR1 at concentrations of diferric Tf lower than 100 nM. 11 These experiments explain the early observation that HFE appears to lower the binding affinity of TfR to diferric Tf. 7,14 Indeed, in HeLa, HEK293, and H1299 cells, expression of exogenous HFE results in the lowering of intracellular iron levels. However, HeLa and H1299 cells expressing HFE have about 30% lower rates of Tf-mediated iron uptake than parental controls, even in the presence of sufficiently high concentrations of diferric Tf that HFE does not affect the uptake of Tf. 15,16 In addition, the W81A HFE mutant regulates Tf-mediated iron uptake to the same extent as wild-type HFE in HeLa cells, 17 despite showing a 5000-fold lower affinity for TfR1 binding. 18 These studies show that the effect of HFE on iron homeostasis does not depend solely on the interaction with TfR1 and is more complex than simple competition between HFE and Tf for binding to TfR1.In this study we took advantage of a Chinese hamster ovary cell line, TRVb cells, which lacks endogenous transferrin receptors. 19 These cells w...

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“…The expression pattern of rat Hfe mRNA and protein has been studied, and two groups have shown, relatively recently, that rat Hfe is more strongly expressed by hepatocytes compared to Kupffer cells (Holmstrom et al, 2003;Zhang et al, 2004). As a result the expression of human HFE has become thought of as being localised to hepatocytes as well.…”

Section: Discussionmentioning

confidence: 99%