Hypoxia Alters Iron-regulatory Protein-1 Binding Capacity and Modulates Cellular Iron Homeostasis in Human Hepatoma and Erythroleukemia Cells

Tóth, Ildikó; Yuan, Liping; Rogers, Jack T.; Boyce, Hayden; Bridges, Kenneth R.

doi:10.1074/jbc.274.7.4467

Cited by 88 publications

(93 citation statements)

References 43 publications

(45 reference statements)

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“…Hemoglobin iron in erythrocytes makes up more than two-thirds of the total iron pool, with storage in the liver accounting for most of the remainder [5]. Much of the body iron resulting from the breakdown of effete erythrocytes by macrophages of the reticuloendothelial system is recycled [3]. An increase in metabolic demand for iron results in both increased intestinal absorption of the metal and the mobilization of iron from tissue stores [5].…”

mentioning

confidence: 99%

“…Most of the iron in humans exists either in storage as ferritin [3] or as heme (iron protoporphyrin IX) [5]. Iron is an essential metal in oxygen transport mediated by hemoglobin.…”

mentioning

confidence: 99%

“…The divalent metal transporter (previously named Nramp2) may be the primary intestinal transporter of the metal [3], and ferroportin exports iron across the basolateral membrane of enterocytes into the circulation after it has been oxidized by membrane-bound ferroxidase [8]. All circulating plasma iron is bound to transferrin [3], and cellular uptake of transferrin-bound iron depends upon the number of membrane-transferring receptors [8].…”

mentioning

confidence: 99%

“…Intestinal absorption of the metal is the most important determinant of the amount of iron in the body at any one time, and hepatocytes are the main storage sites of that iron [1][2][3][4][5][6]. Iron is stored in the core of ferritin as ferric oxyhydroxyapatite, with one molecule of ferritin binding as many as 4,500 molecules of iron [1][2][3]. Hepcidin, the most important regulator of systemic iron metabolism, is influenced by body iron stores, erythropoietic activity, and hypoxia, and plays the dominant role in controlling iron absorption [6,7].…”

mentioning

confidence: 99%

“…Only a small fraction of the total body iron enters or leaves the body on a daily basis [1][2][3][4], with both iron absorption and loss being finely regulated and balanced [5]. Intestinal absorption of the metal is the most important determinant of the amount of iron in the body at any one time, and hepatocytes are the main storage sites of that iron [1][2][3][4][5][6]. Iron is stored in the core of ferritin as ferric oxyhydroxyapatite, with one molecule of ferritin binding as many as 4,500 molecules of iron [1][2][3].…”

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confidence: 99%

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Hepatic iron overload and hepatocellular carcinoma

Kew

2009

Cancer Letters

108

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In recent years it has become increasingly evident that excess body iron may be complicated by the supervention of hepatocellular carcinoma (HCC). Hereditary hemochromatosis (HH) was the first condition in which hepatic iron overload was shown to predispose to the development of HCC. The inherited predisposition to excessive absorption of dietary iron in HH is almost always the result of homozygosity of the C282Y mutation of the HFE gene, which causes inappropriately low secretion of hepcidin. HCC develops in 8-10% of patients with HH and is responsible for approximately 45% of deaths in the HCC patients. Cirrhosis is almost always present when HCC is diagnosed. Dietary iron overload is a condition which occurs in rural-dwelling Black Africans in southern Africa as a result of the consumption, over time, of large volumes of alcohol home-brewed in iron containers and having, as a consequence, a high iron content. Iron loading of the liver results and may be complicated by malignant transformation of the liver (relative risk of approximately 10.0). Accompanying cirrhosis does occur but is less common than that in HH. The development of HCC as a consequence of increased dietary iron, and the fact that it may develop in the absence of cirrhosis, has been confirmed in an animal model. Drinking water with a high iron content might contribute to the high incidence of HCC in parts of Taiwan. The metabolic syndrome [obesity, insulin resistance type 2 (or diabetes mellitus type 2), non-alcoholic fatty liver or non-alcoholic steatohepatitis] has in recent years become a major public health problem in some resource-rich countries. A link between excess body iron and insulin resistance or the metabolic syndrome has become apparent. The metabolic syndrome may be complicated by the supervention of HCC, and recent evidence suggests that increased body iron may contribute to this complication.

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confidence: 99%

“…Most of the iron in humans exists either in storage as ferritin [3] or as heme (iron protoporphyrin IX) [5]. Iron is an essential metal in oxygen transport mediated by hemoglobin.…”

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Hepatic iron overload and hepatocellular carcinoma

Kew

2009

Cancer Letters

108

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Time‐dependent effects of hypoxia on cell metabolism, signaling, and iron homeostasis in the hematopoietic progenitor model KG1a

et al. 2023

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Lowered availability of oxygen in the micro‐environment of cells perturbs metabolic and signaling pathways. It affects proliferation, tissue morphology, and differentiation. Leukemia impairs maturation of hematopoietic progenitors: the immune system, healing, and erythropoiesis are weakened, thereby perturbing iron homeostasis and further lowering oxygen provision to tissues. Here, the time‐dependent molecular consequences of sudden hypoxia were studied in the KG1a model of immature hematopoietic progenitors. The oxygen tension of KG1a cells was abruptly lowered from the experimentally usual ca. 20 to 1%. Growth and key hubs of signaling, metabolism, and iron homeostasis were monitored by a combination of immunological methods and functional assays. The collapse of oxygen availability stopped proliferation after one generation. The number of cells then remained approximately constant over several days, including after anaerobic changes in the culture medium. Lowered oxygen resulted in transient increase of the hypoxia‐inducible factor 1α and of its REDD1 target, inhibition of mechanistic (or mammalian) target of rapamycin, decreased autophagy, altered cap‐dependent translation, and minimal repression of the already weak oxidative phosphorylation. These adjustments did not trigger important cellular iron fluxes since the cells relied on their internal iron stores to survive. In conclusion, the response of the KG1a cells to stringent hypoxia is varied, with some established hypoxia‐sensitive pathways exhibiting activation whereas others were unaffected. The results draw attention to the flexibility of the environmental adaptation of cancer cells. They suggest that thorough characterization of early leukemic blasts is warranted to propose informed treatments to patients.

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Iron Homeostasis in the Liver

Anderson

Shah

2013

Comprehensive Physiology

182

139

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Iron is an essential nutrient that is tightly regulated. A principal function of the liver is the regulation of iron homeostasis. The liver senses changes in systemic iron requirements and can regulate iron concentrations in a robust and rapid manner. The last 10 years have led to the discovery of several regulatory mechanisms in the liver which control the production of iron regulatory genes, storage capacity, and iron mobilization. Dysregulation of these functions leads to an imbalance of iron, which is the primary causes of iron-related disorders. Anemia and iron overload are two of the most prevalent disorders worldwide and affect over a billion people. Several mutations in liver-derived genes have been identified, demonstrating the central role of the liver in iron homeostasis. During conditions of excess iron, the liver increases iron storage and protects other tissues, namely the heart and pancreas from iron-induced cellular damage. However, a chronic increase in liver iron stores results in excess reactive oxygen species production and liver injury. Excess liver iron is one of the major mechanisms leading to increased steatohepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma.

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Hypoxia Alters Iron-regulatory Protein-1 Binding Capacity and Modulates Cellular Iron Homeostasis in Human Hepatoma and Erythroleukemia Cells

Cited by 88 publications

References 43 publications

Hepatic iron overload and hepatocellular carcinoma

Hepatic iron overload and hepatocellular carcinoma

Time‐dependent effects of hypoxia on cell metabolism, signaling, and iron homeostasis in the hematopoietic progenitor model KG1a

Iron Homeostasis in the Liver

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