title: Increased copper levels in in vitro and in vivo models of Niemann-Pick C disease.
abstract: 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.
authors.affiliation: Departamento de Gastroenterología, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile. mc.vazquez.rodriguez@gmail.com
authors.forename: Mary Carmen
authors.initials: MC
authors.lastname: Vázquez
authors.forename: Pablo
authors.initials: P
authors.lastname: Martínez
authors.forename: Alejandra R
authors.initials: AR
authors.lastname: Alvarez
authors.forename: Mauricio
authors.initials: M
authors.lastname: González
authors.forename: Silvana
authors.initials: S
authors.lastname: Zanlungo
mesh_terms: D000736:Androstenes; D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D002570:Ceruloplasmin / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism; D003300:Copper / Q000097:blood* / Q000378:metabolism*; D056945:Hep G2 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D008807:Mice, Inbred BALB C; D000077296:Niemann-Pick C1 Protein; D009542:Niemann-Pick Diseases / Q000097:blood* / Q000378:metabolism*; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D051381:Rats
chemical_list: D000736:Androstenes; D047908:Intracellular Signaling Peptides and Proteins; D000077296:Niemann-Pick C1 Protein; C106831:Npc1 protein, mouse; D011506:Proteins; C006261:3-beta-(2-(diethylamino)ethoxy)androst-5-en-17-one; D003300:Copper; D002784:Cholesterol; D002570:Ceruloplasmin