Regulation of ferritin and transferrin receptor expression by iron in human hepatocyte cultures

Hubert, N.; Lescoat, Gérard; Sciot, Raf; Moirand, Romain; Jégo, Patrick; Leroyer, Patricia; Brissot, Pierre

doi:10.1016/s0168-8278(05)80274-0

Cited by 38 publications

(21 citation statements)

References 44 publications

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“…20 Expression of TfR1 is regulated at the levels of transcription and posttranscription by factors such as cellular status of iron, oxygen, proliferation, and differentiation. [21][22][23][24][25][26] Expression profiles of TfR1 and TfR2 in response to cellular iron status were also different. Intracellular iron levels regulate expression of TfR1 mainly at a posttranscriptional level.…”

Section: Discussionmentioning

confidence: 99%

Regulation of expression of murine transferrin receptor 2

Kawabata

Germain

Ikezoe

et al. 2001

Blood

126

118

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Complementary and genomic DNA for the murine transferrin receptor 2 (TfR2) were cloned and mapped to chromosome 5. Northern blot analysis showed that high levels of expression of murine TfR2 occurred in the liver, whereas expression of TfR1 in the liver was relatively low. During liver development, TfR2 was up-regulated and TfR1 was down-regulated. During erythrocytic differentiation of murine erythroleukemia (MEL) cells induced by dimethylsulfoxide, expression of TfR1 increased, whereas TfR2 decreased. In MEL cells, expression of TfR1 was induced by desferrioxamine, an iron chelator, and it was reduced by ferric nitrate. In contrast, levels of TfR2 were not affected by the cellular iron status. Reporter assay showed that GATA-1, an erythroid-specific transcription factor essential for erythrocytic differentiation at relatively early stages, enhanced TfR2 promoter activity. Interestingly, FOG-1, a cofactor of GATA-1 required for erythrocyte maturation, repressed the enhancement of the activity by GATA-1. Also, CCAAT-enhancer binding protein, which is abundant in liver, enhanced the promoter activity. Thus, tissue distribution of TfR2 was consistent with the reporter assays. Expression profiles of TfR2 were different from those of TfR1, suggesting unique functions for TfR2, which may be involved in iron metabolism, hepatocyte function, and erythrocytic differentiation. IntroductionIron, one of the essential elements of life, is carried by transferrin (Tf) in the serum and absorbed by the cells through transferrin receptor (TfR1)-mediated mechanisms. 1 Diferric Tf in the serum binds to TfR1 on the cell surface, followed by endocytosis of the receptor-ligand complex. HFE is an atypical major histocompatibility complex (MHC) class I molecule that can form a complex with TfR1 on the cell surface and interfere with binding of Tf to TfR1. [2][3][4] Mutations of HFE are thought to be related to hereditary hemochromatosis. After internalization of the Tf-TfR1 complex, iron is released from the Tf-TfR1 complex in the endosome and is transported to the cytoplasm and mitochondria by DMT1/Nramp2, a transmembrane iron transporter. [5][6][7][8] Recently, we cloned human TfR2, another transferrin receptor gene. Two alternatively spliced forms of human TfR2 transcripts were identified: ␣ and ␤. TfR2-␣ was highly expressed in K562, an erythroid leukemia cell line; in liver; and in HepG2, a hepatoma cell line. 9 Increased Tf binding and iron uptake were observed in Chinese hamster ovary cells that had been stably transfected with human TfR2-␣. Although human TfR2-␣ and TfR1 are very similar in their primary structure and Tf-binding property, the expression pattern of TfR2 mRNA is quite different from that of TfR1. We have found that in K562 cells, iron chelation up-regulates TfR1 and down-regulates TfR2, and iron overload down-regulates TfR1 and slightly up-regulates TfR2. 10 TfR1 knockout mice did not survive beyond embryonic day 12.5 because of severe anemia and neurologic abnormalities, which indicates that murine TfR2 cannot ...

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Section: Discussionmentioning

confidence: 99%

Regulation of expression of murine transferrin receptor 2

Kawabata

Germain

Ikezoe

et al. 2001

Blood

126

118

View full text Add to dashboard Cite

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“…The iron uptake by hepatocytes is regulated in response to both the intracellular iron store and the extracellular or plasma iron level. While the uptake of iron by the nonsaturable transferrin uptake processes is not affected by the intracellular iron concentration but is dependent on the extracellular diferric transferrin concentration, the TfR expression and the subsequent uptake of transferrin and iron in hepatocytes is inversely regulated by the intracellular chelatable iron pool [53][54][55], presumably via the iron-responsive elements (IRE) and iron-regulatory protein (IRP) system (see below). In the iron-overloaded liver, as in hereditary hemochromatosis, there is little hepatic TfR expression [56].…”

Section: Hepatocytesmentioning

confidence: 99%

Regulation of Transferrin Function and Expression: Review and Update

Lok¹,

Loh²

1998

Biol Signals Recept

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The cellular iron uptake is a precisely controlled process to fulfill the iron demand for the synthesis and functions of a variety of iron-containing proteins, and one of the main molecules involved is the transferrin receptor (TfR), which mediates the uptake process via the transferrin cycle. The TfR expression is tightly regulated by factors such as intracellular iron level, cell proliferation or erythropoiesis at levels of receptor recycling, transcriptional or posttranscriptional control. The iron-regulatory protein/iron-responsive element system has been widely used to explain changes in receptor expression during iron loading or depletion, oxidative stress and nitric oxide stimulation. On the other hand, transcriptional control of TfR expression appears to be more important in erythroid differentiation and general cell proliferation. There is also an increasing awareness of the clinical application and experimental therapeutics based on the TfR functioning and expression. In this review, we attempt to provide a concise account of the studies of TfR structure and function as well as those areas that have not been reviewed in depth, in particular, tissue-specific regulation of TfR, the molecular mechanisms of TfR expression, and the use of TfR as diagnostic and therapeutic tools. The regulation of TfR expression in various tissues is related to its specific cellular iron requirements. Hemoglobin-synthesizing cells exhibit distinct features of iron metabolism and TfR expression as compared to most non-erythroid cells which synthesize a much lower amount of heme. For most non-erythroid cells, iron can regulate the TfR expression in a reciprocal manner through modulating the stability of the receptor mRNA whereas in hemoglobin-synthesizing cells, the TfR expression is independent of the cellular iron loading. In spite of a wide heterogeneity in the way receptor redistribution is in response to various stimuli, regulation of the constitutive expression of TfR is one of the ways of regulating the cellular iron uptake. This expression operates on both transcriptional and posttranscriptional levels. In general, factors related to cell growth and differentiation operate on the gene transcription level, whereas iron regulates the fate of the mature mRNA.

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“…However, expression of the classical transferrin receptor (TfR) in hepatocytes (as in other nonreticuloendothelial cell types) has been shown to be downregulated in response to increased intracellular iron (4,5). As a consequence, TfR expression in liver is undetectable in HH patients with hepatic iron loading (6)(7)(8).…”

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confidence: 99%

Transferrin receptor 2: Continued expression in mouse liver in the face of iron overload and in hereditary hemochromatosis

Fleming

Migas

Holden

et al. 2000

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

244

166

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Hereditary hemochromatosis (HH) is a common autosomal recessive disorder characterized by excess absorption of dietary iron and progressive iron deposition in several tissues, particularly liver. Liver disease resulting from iron toxicity is the major cause of death in HH. Hepatic iron loading in HH is progressive despite downregulation of the classical transferrin receptor (TfR). Recently a human cDNA highly homologous to TfR was identified and reported to encode a protein (TfR2) that binds holotransferrin and mediates uptake of transferrin-bound iron. We independently identified a full-length murine EST encoding the mouse orthologue of the human TfR2. Although homologous to murine TfR in the coding region, the TfR2 transcript does not contain the ironresponsive elements found in the 3 untranslated sequence of TfR mRNA. To determine the potential role for TfR2 in iron uptake by liver, we investigated TfR and TfR2 expression in normal mice and murine models of dietary iron overload (2% carbonyl iron), dietary iron deficiency (gastric parietal cell ablation), and HH (HFE ؊͞؊).Northern blot analyses demonstrated distinct tissue-specific patterns of expression for TfR and TfR2, with TfR2 expressed highly only in liver where TfR expression is low. In situ hybridization demonstrated abundant TfR2 expression in hepatocytes. In contrast to TfR, TfR2 expression in liver was not increased in iron deficiency. Furthermore, hepatic expression of TfR2 was not downregulated with dietary iron loading or in the HFE ؊͞؊ model of HH. From these observations, we propose that TfR2 allows continued uptake of Tf-bound iron by hepatocytes even after TfR has been down-regulated by iron overload, and this uptake contributes to the susceptibility of liver to iron loading in HH.

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Regulation of ferritin and transferrin receptor expression by iron in human hepatocyte cultures

Cited by 38 publications

References 44 publications

Regulation of expression of murine transferrin receptor 2

Regulation of expression of murine transferrin receptor 2

Regulation of Transferrin Function and Expression: Review and Update

Transferrin receptor 2: Continued expression in mouse liver in the face of iron overload and in hereditary hemochromatosis

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