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

Wilson disease is a genetic disorder characterized by the accumulation of copper in the body by defective biliary copper excretion. Wilson disease gene product (ATP7B) functions in copper incorporation to ceruloplasmin (Cp) and biliary copper excretion. However, copper metabolism in hepatocytes has been still unclear. Niemann-Pick disease type C (NPC) is a lipid storage disorder and the most commonly mutated gene is NPC1 and its gene product NPC1 is a late endosome protein and regulates intracellular vesicle traffic. In the present study, we induced NPC phenotype and examined the localization of ATP7B and secretion of holo-Cp, a copper-binding mature form of Cp. The vesicle traffic was modulated using U18666A, which induces NPC phenotype, and knock down of NPC1 by RNA interference. ATP7B colocalized with the late endosome markers, but not with the trans-Golgi network markers. U18666A and NPC1 knock down decreased holo-Cp secretion to culture medium, but did not affect the secretion of other secretory proteins. Copper accumulated in the cells after the treatment with U18666A. These findings suggest that ATP7B localizes in the late endosomes and that copper in the late endosomes is transported to the secretory compartment via NPC1-dependent pathway and incorporated into apo-Cp to form holo-Cp.
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PMID:Niemann-Pick C1 protein transports copper to the secretory compartment from late endosomes where ATP7B resides. 1900 72

We present a 28-year-old woman with a diagnosis of Niemann-Pick type C disease which was initially diagnosed as Wilson disease due to low serum ceruloplasmin and elevated free copper. This report supports the hypothesis that NPC1 could play a role in copper metabolism.
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PMID:Low ceruloplasmin in a patient with Niemann-Pick type C disease. 2226 6

Niemann-Pick type C disease (NPC) is a hereditary neurovisceral atypical lipid storage disorder produced by mutations in the NPC1 and NPC2 genes. The disease is characterized by unesterified cholesterol accumulation in late endosomal/lysosomal compartments and oxidative stress. The most affected tissues are the cerebellum and the liver. The lysotropic drug U18666A (U18) has been widely used as a pharmacological model to induce the NPC phenotype in several cell culture lines. It has already been reported that there is an increase in copper content in hepatoma Hu7 cells treated with U18. We confirmed this result with another human hepatoma cell line, HepG2, treated with U18 and supplemented with copper in the media. However, in mouse hippocampal primary cultures treated under similar conditions, we did not find alterations in copper content. We previously reported increased copper content in the liver of Npc1 (-/-) mice compared to control animals. Here, we extended the analysis to the copper content in the cerebella, the plasma and the bile of NPC1 deficient mice. We did not observe a significant change in copper content in the cerebella, whereas we found increased copper content in the plasma and decreased copper levels in the bile of Npc1(-/-) mice. Finally, we also evaluated the plasma content of ceruloplasmin, and we found an increase in this primary copper-binding protein in Npc1 (-/-) mice. These results indicate cell-type dependence of copper accumulation in NPC disease and suggest that copper transport imbalance may be relevant to the liver pathology observed in NPC disease.
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PMID:Increased copper levels in in vitro and in vivo models of Niemann-Pick C disease. 2252 61

The loss of NPC1 protein function is the predominant cause of Niemann-Pick type C1 disease (NP-C1), a systemic and neurodegenerative disorder characterized by late-endosomal/lysosomal accumulation of cholesterol and other lipids. Limited evidence from post-mortem human tissues, an Npc1(-/-) mouse model, and cell culture studies also suggest failure of metal homeostasis in NP-C1. To investigate these findings, we performed a comprehensive transition metal analysis of cerebrospinal fluid (CSF), plasma and tissue samples from human NP-C1 patients and an Npc1(-/-) mouse model. NPC1 deficiency in the Npc1(-/-) mouse model resulted in a perturbation of transition metal homeostasis in the plasma and key organs (brain, liver, spleen, heart, lungs, and kidneys). Analysis of human patient CSF, plasma and post-mortem brain tissues also indicated disrupted metal homeostasis. There was a disparity in the direction of metal changes between the human and the Npc1(-/-) mouse samples, which may reflect species-specific metal metabolism. Nevertheless, common to both species is brain zinc accumulation. Furthermore, treatment with the glucosylceramide synthase inhibitor miglustat, the only drug shown in a controlled clinical trial to have some efficacy for NP-C1, did not correct the alterations in CSF and plasma transition metal and ceruloplasmin (CP) metabolism in NP-C1 patients. These findings highlight the importance of NPC1 function in metal homeostasis, and indicate that metal-targeting therapy may be of value as a treatment for NP-C.
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PMID:Altered transition metal homeostasis in Niemann-Pick disease, type C1. 2434 24

Niemann-Pick C disease (NPC) is a vesicular trafficking disorder primarily caused by mutations in the Npc1 gene and characterized by liver dysfunction and neuropathology. Altered hepatic copper metabolism has recently been reported in NPC disease. Therefore, we aimed to analyze the effects of a copper deficient diet and copper chelation using d-penicillamine on copper homeostasis in the liver of Npc1(-/-) mice of different ages. We examined liver metal ion content by AAS, and copper and iron metabolism gene expression in the liver using qPCR in Npc1(+/+) and Npc1(-/-) mice. We found higher copper and lower iron content in the liver of Npc1(-/-) mice of different ages, compared to controls; these changes in copper and iron content were correlated with increased ceruloplasmin, metallothionein 1, and transferrin receptor gene expression and decreased gene expression of Commd1, ferritin-light chain and ferroportin in the liver of Npc1(-/-) mice of different ages. Npc1(-/-) mice responded to a copper-deficient diet with a decrease in copper content in the liver, bile and heart. These results correlated with a reduction in the hepatic expression of ceruloplasmin and metallothionein 1 during the first week of treatment. d-penicillamine revealed hepatic adaptive response and an improvement in hepatic function in Npc1(-/-) mice without any effect on neurological functions. Our results confirm that the NPC1 protein is required for copper and iron homeostasis. To our knowledge, this is the first report documenting the hepatic adaptive response to low-copper intake in a Npc1(-/-) mouse model.
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PMID:Hepatic metabolic response to restricted copper intake in a Niemann-Pick C murine model. 2490 80