Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:1.16.3.1 (ceruloplasmin)
 5,074 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The application of molecular genetics to haemochromatosis and experimental mutagenesis in animals has transformed our capacity to investigate the unique physiology of iron homeostasis-a key problem in biology and medicine. The identification of HFE, the principal determinant of adult haemochromatosis (HFE1; OMIM 235200) and TfR2, recently implicated in a rarer form of the inherited disorder (HFE3; OMIM 604250), and the promise of candidate genes for juvenile haemochromatosis (HFE2; OMIM 602390) and neonatal haemochromatosis (OMIM 231100) provide the foundation for important studies into the control mechanism of iron balance in humans. The rare conditions atransferrinaemia (OMIM 209300) and acaeruloplasminaemia (OMIM 604290), each associated with tissue iron overload, have already implicated the iron transport ligand transferrin and the copper transporter caeruloplasmin in the control of iron homeostasis. Gene mapping studies in animal mutants with anaemia due to defects in the uptake or tissue transfer of iron have yielded novel proteins involved in iron transport: DMT1 (brush border transporter of ferrous iron) in the mk/mk mouse, hephaestin (basolateral multi-copper ferroxidase) in the sex-linked anaemic mouse (sla) and ferroportin1 (basolateral iron exporter) in zebrafish weh mutants. The discovery of genes that determine heritable defects of iron absorption and regulation in animals and humans thus holds promise for a complete mechanistic understanding of the molecular pathophysiology of iron metabolism.
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PMID:Haemochromatosis: novel gene discovery and the molecular pathophysiology of iron metabolism. 1100 92

Hephaestin is a membrane-bound multicopper ferroxidase necessary for iron egress from intestinal enterocytes into the circulation. Mice with sex-linked anemia (sla) have a mutant form of Hephaestin and a defect in intestinal basolateral iron transport, which results in iron deficiency and anemia. Ireg1 (SLC11A3, also known as Ferroportin1 or Mtp1) is the putative intestinal basolateral iron transporter. We compared iron levels and expression of genes involved in iron uptake and storage in sla mice and C57BL/6J mice fed iron-deficient, iron-overload, or control diets. Both iron-deficient wild-type mice and sla mice showed increased expression of Heph and Ireg1 mRNA, compared to controls, whereas only iron-deficient wild-type mice had increased expression of the brush border transporter Dmt1. Unlike iron-deficient mice, sla mouse enterocytes accumulated nonheme iron and ferritin. These results indicate that Dmt1 can be modulated by the enterocyte iron level, whereas Hephaestin and Ireg1 expression respond to systemic rather than local signals of iron status. Thus, the basolateral transport step appears to be the primary site at which the small intestine responds to alterations in body iron requirements.
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PMID:Systemic regulation of Hephaestin and Ireg1 revealed in studies of genetic and nutritional iron deficiency. 1273 Jan 11

Release of iron from enterocytes and hepatocytes is thought to require the copper-dependent ferroxidase activity of hephaestin (Hp) and ceruloplasmin (Cp), respectively. In swine, copper deficiency (CD) impairs iron absorption, but whether this occurs in rats is unclear. By feeding a diet deficient in copper, CD was produced, as evidenced by the loss of copper-dependent plasma ferroxidase I activity, and in enterocytes, CD reduced copper levels and copper-dependent oxidase activity. Hematocrit was reduced, and liver iron was doubled. CD reduced duodenal mucosal iron and ferritin, whereas CD increased iron absorption. Duodenal mucosal DMT1-IRE and ferroportin1 expression remained constant with CD. When absorption in CD rats was compared with that seen normally and in iron-deficient anemic animals, strong correlations were found among mucosal iron, ferritin, and iron absorption, suggesting that the level of iron absorption was appropriate given that the erythroid and stores stimulators of iron absorption are opposed in CD. Because CD reduced the activity of Cp, as evidenced by copper-dependent plasma ferroxidase I activity and hepatocyte iron accumulation, but iron absorption increased, it is unlikely that the ferroxidase activity of Hp is important and suggests another function for this protein in the export of iron from the enterocyte during iron absorption. Also, the copper-dependent ferroxidase activity of Cp does not appear important for iron efflux from macrophages, because Kupffer cells of the liver and nonheme iron levels of the spleen were normal during copper deficiency, suggesting another role for Cp in these cells.
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PMID:Copper deficiency increases iron absorption in the rat. 1276 Sep 4

Copper and iron metabolism intersect in mammals. Copper deficiency simultaneously leads to decreased iron levels in some tissues and iron deficiency anemia, whereas it results in iron overload in other tissues such as the intestine and liver. The copper requirement of the multicopper ferroxidases hephaestin and ceruloplasmin likely explains this link between copper and iron homeostasis in mammals. We investigated the effect of in vivo and in vitro copper deficiency on hephaestin (Heph) expression and activity. C57BL/6J mice were separated into 2 groups on the day of parturition. One group was fed a copper-deficient diet and another was fed a control diet for 6 wk. Copper-deficient mice had significantly lower hephaestin and ceruloplasmin (approximately 50% of controls) ferroxidase activity. Liver hepcidin expression was significantly downregulated by copper deficiency (approximately 60% of controls), and enterocyte mRNA and protein levels of ferroportin1 were increased to 2.5 and 10 times, respectively, relative to controls, by copper deficiency, indicating a systemic iron deficiency in the copper-deficient mice. Interestingly, hephaestin protein levels were significantly decreased to approximately 40% of control, suggesting that decreased enterocyte copper content leads to decreased hephaestin synthesis and/or stability. We also examined the effect of copper deficiency on hephaestin in vitro in the HT29 cell line and found dramatically decreased hephaestin synthesis and activity. Both in vivo and in vitro studies indicate that copper is required for the proper processing and/or stability of hephaestin.
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PMID:Decreased hephaestin activity in the intestine of copper-deficient mice causes systemic iron deficiency. 1661 10

It has been suggested that Hephaestin (Heph), a newly discovered ceruloplasmin homologue, is necessary for iron egress from the enterocytes into circulation via interacting with ferroportin1 (FP1). Based on the putative function of Heph, and the similarity between the process of iron transport in the enterocytes and that in the blood-brain barrier (BBB) cells, it has also been proposed that Heph plays a similar role in exporting iron from the BBB cells and other brain cells as it works in the enterocytes via interacting with FP1. The existence of FP1 in the brain has been demonstrated. In this study, we investigated Heph expression and effects of development and iron in the cortex, hippocampus, striatum, and substantia nigra. The data demonstrated that all the four regions we examined have the ability to express Heph mRNA and protein. The findings also showed that both the development and iron status have a significant effect on Heph expression and the effects of iron status are regionally specific. It was also suggested that Heph expression is probably regulated at the transcriptional level by the development and iron in these brain regions. These findings, together with other published data, support a putative role of Heph in the iron metabolism in the brain.
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PMID:Development and iron-dependent expression of hephaestin in different brain regions of rats. 1751 1

Iron is transported across intestinal brush border cells into the circulation in at least two distinct steps. Iron can enter the enterocyte via the apical surface through several paths. However, iron egress from the basolateral side of enterocytes converges on a single export pathway requiring the iron transporter, ferroportin1, and hephaestin, a ferroxidase. Copper deficiency leads to reduced hephaestin protein expression and activity in mouse enterocytes and intestinal cell lines. We tested the effect of copper deficiency on differentiated Caco2 cells grown in transwells and found decreased hephaestin protein expression and activity as well as reduced ferroportin1 protein levels. Furthermore, the decrease in hephaestin levels correlates with a decrease of (55)Fe release from the basolateral side of Caco2 cells. Presence of ceruloplasmin, apo-transferrin or holo-transferrin did not significantly alter the results observed. Repletion of copper in Caco2 cells leads to reconstitution of hephaestin protein expression, activity, and transepithelial iron transport.
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PMID:Decreased hephaestin expression and activity leads to decreased iron efflux from differentiated Caco2 cells. 1945 51

Iron is an essential nutrient, but its concentration and distribution in the body must be tightly controlled due to its inherent toxicity and insolubility in aqueous solution. Living systems have successfully overcome these potential limitations by evolving a range of iron binding proteins and transport systems that effectively maintain iron in a nontoxic and soluble form for much, if not all, of its time within the body. In the circulation, iron is transported to target organs bound to the serum iron binding protein transferrin. Individual cells modulate their uptake of transferrin-bound iron depending on their iron requirements, using both transferrin receptor 1-dependent and independent pathways. Once inside the cell, iron can be chaperoned to sites of need or, if in excess, stored within ferritin. Iron is released from cells by the iron export protein ferroportin1, which requires the ferroxidase activity of ceruloplasmin or hephestin to load iron safely onto transferrin. The regulation of iron export is controlled predominantly at the systemic level by the master regulator of iron homeostasis hepcidin. Hepcidin, in turn, responds to changes in body iron demand, making use of a range of regulatory mechanisms that center on the bone morphogenetic protein signaling pathway. This review provides an overview of recent advances in the field of iron metabolism and outlines the key components of the iron transport and regulation systems.
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PMID:The regulation of iron transport. 2413 7

Elevated iron levels in the substantia nigra (SN) participate in neuronal death in Parkinson's disease (PD), while the mechanisms underlying the increased iron are still unknown. Ceruloplasmin (CP), a ferroxidase, converts highly toxic ferrous iron to its non-toxic ferric form, which cooperated with ferroportin1 (FP1) facilitating the export of iron from cells. To elucidate if the abnormal expression of CP is involved in the nigral iron accumulation, here, we investigated CP expression in the SN of rats lesioned by 6-hydroxydopamine (6-OHDA). We showed that FP1 and CP colocalized in the rat SN. One day after 6-OHDA lesion, when there was a half reduction in the number of dopaminergic neurons, the iron level was increased compared with the normal rats; both the mRNA and protein expressions of CP decreased compared with the control. When rats began showing rotation behavior induced by apomorphine, usually after 6 weeks since 6-OHDA lesion, they are considered PD models. In these PD models, almost no dopaminergic neurons can be detected in the lesioned SN and nigral iron level was further increased. At this time point, a further decrease of CP was observed. These results show that FP1 and CP colocalize in the rat brain, indicating the coordinated actions of the two proteins in the cellular iron export, and suggest that decreased expression of CP in the SN is involved in the nigral iron accumulation of 6-OHDA-lesioned rats.
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PMID:Ceruloplasmin is Involved in the Nigral Iron Accumulation of 6-OHDA-Lesioned Rats. 2565 40