Regulation of transferrin, transferrin receptor, and ferritin genes in human duodenum

Pietrangelo, Antonello; Rocchi, Emilio; Casalgrandi, Giovanna; Rigo, Gianpiero; Ferrari, Alberto; Perini, Mario; Ventura, Ezio; Cairo, Gaetano

doi:10.1016/0016-5085(92)90161-q

Cited by 146 publications

(55 citation statements)

References 36 publications

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“…Because HFE knockout and C282Y mutant mice behave phenotypically like ␤ 2 M-deficient mice, i.e., both have the murine HH phenotype, one would predict that they would (11)(12)(13)(14)(15). By analogy with the role of HFE-␤ 2 M in modulating uptake of Tf-Fe by CHO and TRVb-1 cells, we suggest: (i) that HFE-␤ 2 M normally plays a role in facilitating uptake of Tf-bound iron by duodenal crypt cells and macrophages; (ii) that HFE mutations that impair this function in HH patients contribute to dysregulation of iron absorption, because this uptake process by duodenal crypt cells is key to sensing the level of Tf-bound iron in capillaries surrounding crypt cells of the duodenum where iron absorption is controlled (48,50,51); and (iii) this impairment of Tf-bound iron uptake leads the duodenal crypt cells to be iron poor (47)(48)(49)52), even in the face of body iron excess, and to program cells differentiating into mature villus cells to absorb excess iron in HH. Supporting this model, HH patients have increased duodenal expression of the apical iron transporter, divalent metal transporter 1, and the basolateral iron transporter ferroportin 1 (49,52).…”

Section: Discussionmentioning

confidence: 98%

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Regulation of transferrin-mediated iron uptake by HFE, the protein defective in hereditary hemochromatosis

Waheed

Grubb

Zhou

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

124

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The protein defective in hereditary hemochromatosis, called HFE, is similar to MHC class I-type proteins and associates with ␤2-microglobulin (␤2M). Its association with ␤2M was previously shown to be necessary for its stability, normal intracellular processing, and cell surface expression in transfected COS cells. Here we use stably transfected Chinese hamster ovary cell lines expressing both HFE and ␤ 2 M or HFE alone to study the effects of ␤ 2 M on the stability and maturation of the HFE protein and on the role of HFE in transferrin receptor 1 (TfR1)-mediated iron uptake. In agreement with prior studies on other cell lines, we found that overexpression of HFE, without overexpressing ␤2M, resulted in a decrease in TfR1-dependent iron uptake and in lower iron levels in the cells, as evidenced by ferritin and TfR1 levels measured at steady state. However, overexpression of both HFE and ␤2M had the reverse effect and resulted in an increase in TfR1-dependent iron uptake and increased iron levels in the cells. The HFE-␤2M complex did not affect the affinity of TfR1 for transferrin or the internalization rate of transferrin-bound TfR1. Instead, HFE-␤2M enhanced the rate of recycling of TfR1 and resulted in an increase in the steady-state level of TfR1 at the cell surface of stably transfected cells. We propose that Chinese hamster ovary cells provide a model to explain the effect of the HFE-␤2M complex in duodenal crypt cells, where the HFE-␤2M complex appears to facilitate the uptake of transferrin-bound iron to sense the level of body iron stores. Impairment of this process in duodenal crypt cells leads them to be iron poor and to signal the differentiating enterocytes to take up iron excessively after they mature into villus cells in the duodenum of hereditary hemochromatosis patients.H ereditary hemochromatosis (HH) is an autosomal recessive disorder of iron metabolism, characterized by excessive absorption of dietary iron in the small intestine. The excess iron is stored in the parenchymal cells of major tissues, primarily the liver, pancreas, heart, pituitary, and joints, eventually leading to severe tissue damage (1-3). The pathogenesis of HH is thought to involve a defect in the mechanism controlling iron absorption in the small intestine (4).The gene defective in hemochromatosis, HFE, encodes an MHC class I-type protein (5). In multiple population studies, 85-90% of HH patients of northern European ancestry were found to be homozygous for the C282Y mutation in HFE. About 5% are compound heterozygotes for C282Y and a second mutation, H63D (5-10). Even earlier, the observation that ␤ 2 -microglobulin (␤ 2 M)-deficient mice develop progressive iron overload similar to that seen in HH patients suggested the involvement of an MHC class I protein in HH (11, 12). Confirmation that mutations in HFE cause HH was provided by observations of mice with targeted disruption of the HFE gene. These HFE knockout mice showed high transferrin saturation and an increase in iron storage in hepatocytes (13-15).The C282Y mutati...

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Section: Discussionmentioning

confidence: 98%

“…might predict from their degree of iron overload (48,49). Macrophages from HH patients show a similarly inappropriate low iron status, despite systemic iron overload (32).…”

Section: Discussionmentioning

confidence: 99%

Regulation of transferrin-mediated iron uptake by HFE, the protein defective in hereditary hemochromatosis

Waheed

Grubb

Zhou

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

124

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“…Divalent Metal Transporter-1 (DMT1/Nramp2/SLC11A2) has been suggested to be the Mn transporter in the duodenum in the adult. Conflicting arguments exist over whether Tf receptors are present or absent in the entrerocyte (Parmley et al, 1985;Pietrangelo et al, 1992(Oates et al, 2000. Studies by Conrad et al indicate that Mn shares the ferrous iron transport mechanism (DMT1) but no the ferric pathway (β 3 -integran and mobilferrin) (Conrad et al, 2000).…”

Section: Divalent Metal Transporter (Dmt1) In Mn Transportmentioning

confidence: 99%

Manganese neurotoxicity: A focus on the neonate

Erikson

Thompson

Aschner

et al. 2007

Pharmacology & Therapeutics

224

141

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Manganese (Mn) is an essential trace metal found in all tissues, and it is required for normal amino acid, lipid, protein, and carbohydrate metabolism. While Mn deficiency is extremely rare in humans, toxicity due to overexposure of Mn is more prevalent. The brain appears to be especially vulnerable. Mn neurotoxicity is most commonly associated with occupational exposure to aerosols or dusts that contain extremely high levels (> 1-5 mg Mn/m 3 ) of Mn, consumption of contaminated well water, or parenteral nutrition therapy in patients with liver disease or immature hepatic functioning such as the neonate. This review will focus primarily on the neurotoxicity of Mn in the neonate. We will discuss putative transporters of the metal in the neonatal brain and then focus on the implications of high Mn exposure to the neonate focusing on typical exposure modes (e.g., dietary and parenteral). Although Mn exposure via parenteral nutrition is uncommon in adults, in premature infants, it is more prevalent, so this mode of exposure becomes salient in this population. We will briefly review some of the mechanisms of Mn neurotoxicity and conclude with a discussion of ripe areas for research in this underreported area of neurotoxicity.

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“…One assumes a generalized defect in iron storage in the RE system and in the feedback regulation of iron absorption (37). The other hypothesis assumes a direct role of the intestinal mucosal cells in regulating iron absorption (63)(64)(65)(66)(67)(68).…”

Section: Molecular Nature Of the Defectmentioning

confidence: 99%

Defective iron homeostasis in beta 2-microglobulin knockout mice recapitulates hereditary hemochromatosis in man.

Santos¹,

Schilham²,

Rademakers³

et al. 1996

The Journal of Experimental Medicine

181

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Previously, hepatic iron overload resembling that in hereditary hemachromatosis (HH) has been found in beta 2-microglobulin knockout (beta 2m-/-) mice. We have now characterized iron metabolism in beta 2m-/- mice. The mutant mice fail to limit the transfer of iron from mucosal cells into the plasma. Transferrin saturation is abnormally high. Pathologic iron depositions occur predominantly in liver parenchymal cells. Reconstitution with normal hematopoietic cells redistributes the iron from parenchymal to Kupffer cells, but does not correct the mucosal defect. We conclude that (a) iron metabolism is defective in the gut mucosa as well as the liver of beta 2m-/- mice; and (b) a beta 2m-dependent gene product is involved in iron homeostasis. Recently, a novel gene of the major histocompatibility complex class I family, HLA-H, has been found to be mutated in a large proportion of HH patients. Our data provide functional support for the proposed causative role of HLA-H mutations in HH.

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Regulation of transferrin, transferrin receptor, and ferritin genes in human duodenum

Cited by 146 publications

References 36 publications

Regulation of transferrin-mediated iron uptake by HFE, the protein defective in hereditary hemochromatosis

Regulation of transferrin-mediated iron uptake by HFE, the protein defective in hereditary hemochromatosis

Manganese neurotoxicity: A focus on the neonate

Defective iron homeostasis in beta 2-microglobulin knockout mice recapitulates hereditary hemochromatosis in man.

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