Regulation of intestinal non-haem iron absorption.

Lombard, Martin; Chua, Eddy; O'Toole, P.A.

doi:10.1136/gut.40.4.435

Cited by 71 publications

(55 citation statements)

References 67 publications

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“…Studies have shown that there is zonal specialization in the handling of iron in the small intestine, with the mature epithelial cells of the mid to upper villus being the site of dietary iron absorption, while the cells of the intestinal crypts are able to transport iron from the circulation via transferrin receptors (16). Therefore, it appears that it is the crypt cells that are responsive to the body's demands for iron and are the site of regulation of iron absorption, although the capability for iron absorption is only expressed after these cells migrate to and become mature enterocytes in the villus.…”

Section: Discussionmentioning

confidence: 99%

“…However, Parkkila et al (15) showed recently by immunohistochemistry that the HFE protein is expressed in certain epithelial cells throughout the human alimentary tract and has a unique localization in the small intestine, where signals to alter iron absorption are received from the body and these signals are translated into an absorption response after the cells have differentiated into mature absorptive enterocytes (16). These observations suggested a possible role for HFE protein in regulating iron absorption in the small intestine.…”

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confidence: 99%

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Hereditary hemochromatosis: Effects of C282Y and H63D mutations on association with β ₂ -microglobulin, intracellular processing, and cell surface expression of the HFE protein in COS-7 cells

Waheed

Parkkila

Zhou

et al. 1997

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

361

233

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Hereditary hemochromatosis (HH) is the most common autosomal recessive disorder known in humans. A candidate gene for HH called HFE has recently been cloned that encodes a novel member of the major histocompatibility complex class I family. Most HH patients are homozygous for a Cys-2823Tyr (C282Y) mutation in HFE gene, which has been shown to disrupt interaction with ␤ 2 -microglobulin; a second mutation, His-633Asp (H63D), is enriched in HH patients who are heterozygous for C282Y mutation. The aims of this study were to determine the effects of the C282Y and H63D mutations on the cellular trafficking and degradation of the HFE protein in transfected COS-7 cells. The results indicate that, while the wild-type and H63D HFE proteins associate with ␤ 2 -microglobulin and are expressed on the cell surface of COS-7 cells, these capabilities are lost by the C282Y HFE protein. We present biochemical and immunof luorescence data that indicate that the C282Y mutant protein: (i) is retained in the endoplasmic reticulum and middle Golgi compartment, (ii) fails to undergo late Golgi processing, and (iii) is subject to accelerated degradation. The block in intracellular transport, accelerated turnover, and failure of the C282Y protein to be presented normally on the cell surface provide a possible basis for impaired function of this mutant protein in HH.Hereditary hemochromatosis (HH) is a common autosomal recessive disorder characterized by iron overload of parenchymal cells in many organs including the liver, pancreas, heart, joints, and endocrine organs due to increased iron absorption in the gastrointestinal tract (1-4). Clinical consequences of iron accumulation in these organs include cirrhosis of the liver, hepatocellular carcinoma, diabetes, heart failure, arthritis, and hypogonadism. Within the Caucasian population, 1 in 300-400 individuals is homozygous and 1 in 8-10 individuals is heterozygous for HH (3,5). Recently, Feder et al. (6) reported that 83% of 178 American HH patients were homozygous for the same missense mutation (C282Y) in a novel major histocompatibility complex (MHC) class I-like gene, originally called HLA-H, but now designated HFE (7). [Although Feder et al. (6) originally designated the HH candidate gene HLA-H, this designation had already been assigned to a pseudogene and the HH locus had already been assigned the name HFE by the nomenclature committee (7).] Eight of nine patients with HH who were heterozygous for this mutation were found to have a different missense mutation (H63D) on the other HFE allele, although 17% of the normal population also carried one H63D allele. These findings were confirmed by Beutler et al. (8), who found that 82% of 147 HH patients were homozygous for the C282Y mutation and 10 were compound heterozygotes for C282Y and H63D alleles. Subsequent studies reported that 72-91% of French patients (9, 10), 64% of Italian patients (11), and 100% of Australian patients (12) were homozygous for the C282Y mutation. Independent support for HFE as the HH gene comes ...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Hereditary hemochromatosis: Effects of C282Y and H63D mutations on association with β ₂ -microglobulin, intracellular processing, and cell surface expression of the HFE protein in COS-7 cells

Waheed

Parkkila

Zhou

et al. 1997

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

361

233

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“…Dietary iron absorption is normally tightly linked with body utilization through the sensing of body iron status in the proximal small intestine (16,17). Several lines of evidence indicate that the body iron status is detected by the uptake of transferrin-bound iron from plasma at the basolateral surface of intestinal crypt cells (18,19).…”

Section: Introductionmentioning

confidence: 99%

“…Although loss of this downregulation of transferrin-mediated iron transport might explain the excess deposition of tissue iron in HH patients, it would not explain the excess absorption of dietary iron (15). Studies on HH patients suggest that the primary defect is loss of the normal feedback mechanisms regulating absorption of dietary (nontransferrin-bound) iron across the intestinal mucosa (2-5).Dietary iron absorption is normally tightly linked with body utilization through the sensing of body iron status in the proximal small intestine (16,17). Several lines of evidence indicate that the body iron status is detected by the uptake of transferrin-bound iron from plasma at the basolateral surface of intestinal crypt cells (18,19).…”

mentioning

confidence: 99%

Mechanism of increased iron absorption in murine model of hereditary hemochromatosis: Increased duodenal expression of the iron transporter DMT1

Fleming

Migas

Zhou

et al. 1999

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

261

154

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Hereditary hemochromatosis (HH) is a common autosomal recessive disorder characterized by tissue iron deposition secondary to excessive dietary iron absorption. We recently reported that HFE, the protein defective in HH, was physically associated with the transferrin receptor (TfR) in duodenal crypt cells and proposed that mutations in HFE attenuate the uptake of transferrin-bound iron from plasma by duodenal crypt cells, leading to up-regulation of transporters for dietary iron. Here, we tested the hypothesis that HFE ؊/؊ mice have increased duodenal expression of the divalent metal transporter (DMT1). Hereditary hemochromatosis (HH) is a common disorder of iron homeostasis in which the intestinal absorption of iron is excessive in relation to body iron status (1-5). The excess iron is deposited in the parenchyma of many tissues, leading to tissue damage and organ failure. Clinical consequences include liver cirrhosis, hepatocellular carcinoma, diabetes, heart failure, arthritis, and hypogonadism (6-9). The gene defective in HH, designated HFE, was found to encode a major histocompatibility complex (MHC) class I-like integral membrane protein (10) that had no obvious relationship to iron absorption. A link between HFE and iron metabolism was provided by the observations in human placenta that the HFE protein is localized on the apical surface of syncytiotrophoblast cells (the site of transferrin-mediated maternal-fetal iron transport) and is physically associated with the transferrin receptor (TfR) (11). Physical association between TfR and expressed recombinant HFE protein was also reported in cultured cells (12, 13) and in vitro (14). In cell culture, overexpressed recombinant HFE (but not HFE carrying the HH mutation) was reported to reduce the affinity of TfR for holotransferrin, suggesting a role for normal HFE in down-regulating transferrin-mediated iron uptake. Although loss of this downregulation of transferrin-mediated iron transport might explain the excess deposition of tissue iron in HH patients, it would not explain the excess absorption of dietary iron (15). Studies on HH patients suggest that the primary defect is loss of the normal feedback mechanisms regulating absorption of dietary (nontransferrin-bound) iron across the intestinal mucosa (2-5).Dietary iron absorption is normally tightly linked with body utilization through the sensing of body iron status in the proximal small intestine (16,17). Several lines of evidence indicate that the body iron status is detected by the uptake of transferrin-bound iron from plasma at the basolateral surface of intestinal crypt cells (18,19). We recently demonstrated that HFE colocalizes with and is physically associated with TfR in these cells (1). This observation suggests a mechanism by which HFE might participate in sensing body iron status by modulating transferrin-mediated uptake of plasma iron in the crypt cells. We propose that mutations of HFE in HH patients impair transferrin-mediated iron uptake and thus decrease crypt cell uptake of plasm...

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“…6,7 A more likely mechanism is decreased iron absorption from hypo or achlorhydria resulting from chronic gastritis. 8 Person with H. pylori infection and IDA appear more likely to have corpus gastritis as compared to H. pylori infected patients without anaemia, which results in decreased gastric acid secretion and increase in intragastric pH that may impair iron absorption. 9,10 Another important effect of H. pylori gastritis that may cause reduced iron absorption is a decrease in gastric juice ascorbic acid concentration, 11,12 increased hepcidin production from hepatocytes in response to IL-6 production associated with H. pylori gastritis.…”

Section: Hb (Gm%)mentioning

confidence: 99%

Role of Anti-Helicobacter Pylori Therapy in Iron Deficiency Anaemia- A Prospective Study

Parambil¹,

Shahulhameed²

2017

jemds

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BACKGROUNDAccumulating evidence suggests that Helicobacter pylori (H. Pylori) infection account for many unexplained cases of Iron Deficiency Anaemia (IDA), which may benefit from testing and treatment for H. pylori infection. This study attempts to evaluate the role of anti H. pylori treatment in management of iron deficiency anaemia among patients treated at a tertiary care centre in North India. MATERIALS AND METHODSThis was a prospective study which included 60 patients with IDA, proven positive for H. pylori by Rapid urease test and histopathological staining. They were divided into three groups (n= 20) and received different treatments, i.e. only anti-H. pylori therapy/ oral iron therapy plus anti-H. pylori therapy/ only oral iron therapy. Haemoglobin, RBC indices, Reti count, S. iron and S. ferritin were compared at the end of treatment with One-Way ANOVA.

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Regulation of intestinal non-haem iron absorption.

Cited by 71 publications

References 67 publications

Hereditary hemochromatosis: Effects of C282Y and H63D mutations on association with β ₂ -microglobulin, intracellular processing, and cell surface expression of the HFE protein in COS-7 cells

Hereditary hemochromatosis: Effects of C282Y and H63D mutations on association with β ₂ -microglobulin, intracellular processing, and cell surface expression of the HFE protein in COS-7 cells

Mechanism of increased iron absorption in murine model of hereditary hemochromatosis: Increased duodenal expression of the iron transporter DMT1

Role of Anti-Helicobacter Pylori Therapy in Iron Deficiency Anaemia- A Prospective Study

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Regulation of intestinal non-haem iron absorption.

Cited by 71 publications

References 67 publications

Hereditary hemochromatosis: Effects of C282Y and H63D mutations on association with β 2 -microglobulin, intracellular processing, and cell surface expression of the HFE protein in COS-7 cells

Hereditary hemochromatosis: Effects of C282Y and H63D mutations on association with β 2 -microglobulin, intracellular processing, and cell surface expression of the HFE protein in COS-7 cells

Mechanism of increased iron absorption in murine model of hereditary hemochromatosis: Increased duodenal expression of the iron transporter DMT1

Role of Anti-Helicobacter Pylori Therapy in Iron Deficiency Anaemia- A Prospective Study

Contact Info

Product

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Hereditary hemochromatosis: Effects of C282Y and H63D mutations on association with β ₂ -microglobulin, intracellular processing, and cell surface expression of the HFE protein in COS-7 cells

Hereditary hemochromatosis: Effects of C282Y and H63D mutations on association with β ₂ -microglobulin, intracellular processing, and cell surface expression of the HFE protein in COS-7 cells