Gpnmb Is a Potential Marker for the Visceral Pathology in Niemann-Pick Type C Disease

Impaired function of NPC1 or NPC2 lysosomal proteins leads to the intracellular accumulation of unesterified cholesterol, the primary defect underlying Niemann-Pick type C (NPC) disease. In addition, glycosphingolipids (GSLs) accumulate in lysosomes as well. Intralysosomal lipid accumulation trigger...

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Vydané v:	PloS one Ročník 11; číslo 1; s. e0147208
Hlavní autori:	Marques, André R. A., Gabriel, Tanit L., Aten, Jan, van Roomen, Cindy P. A. A., Ottenhoff, Roelof, Claessen, Nike, Alfonso, Pilar, Irún, Pilar, Giraldo, Pilar, Aerts, Johannes M. F. G., van Eijk, Marco
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	United States Public Library of Science 15.01.2016 Public Library of Science (PLoS)
Predmet:	Accumulation Adult Aged Aged, 80 and over Animal tissues Animals Biochemistry Bioindicators Biomarkers Biomarkers - metabolism Brain diseases Care and treatment Cell Line Ceramide glucosyltransferase Cholesterol Cholesterol - metabolism Development and progression Disease Models, Animal Eye Proteins - genetics Eye Proteins - metabolism Female Foam Cells - metabolism Genetic disorders Glycoproteins Glycosphingolipids Glycosphingolipids - metabolism Humans Inborn errors of metabolism Laboratories Lipids Liver Lysosomes Macrophages Male Melanoma Membrane Glycoproteins - genetics Membrane Glycoproteins - metabolism Metabolic disorders Metabolism Mice Middle Aged Mucopolysaccharides Niemann-Pick disease Niemann-Pick Disease, Type C - genetics Niemann-Pick Disease, Type C - metabolism Npc1 protein Pathology Patient outcomes Proteins Risk factors Rodents Secretion Transcription Viscera Yang, Cindy Young Adult United States Netherlands Spain
ISSN:	1932-6203, 1932-6203
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Shrnutí:	Impaired function of NPC1 or NPC2 lysosomal proteins leads to the intracellular accumulation of unesterified cholesterol, the primary defect underlying Niemann-Pick type C (NPC) disease. In addition, glycosphingolipids (GSLs) accumulate in lysosomes as well. Intralysosomal lipid accumulation triggers the activation of a set of genes, including potential biomarkers. Transcript levels of Gpnmb have been shown to be elevated in various tissues of an NPC mouse model. We speculated that Gpnmb could serve as a marker for visceral lipid accumulation in NPC disease. We report that Gpnmb expression is increased at protein level in macrophages in the viscera of Npc1nih/nih mice. Interestingly, soluble Gpnmb was also found to be increased in murine and NPC patient plasma. Exposure of RAW264.7 macrophages to the NPC-phenotype-inducing drug U18666A also upregulated Gpnmb expression. Inhibition of GSL synthesis with the glucosylceramide synthase (GCS) inhibitor N-butyl-1-deoxynojirimycin prevented U18666A-induced Gpnmb induction and secretion. In summary, we show that Gpnmb is upregulated in NPC mice and patients, most likely due to GSL accumulation.
Bibliografia:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 Conceived and designed the experiments: ARAM TLG JMFGA MvE. Performed the experiments: ARAM TLG JA CPAAvR RO NC PI PA PG MvE. Analyzed the data: ARAM TLG JA MvE. Contributed reagents/materials/analysis tools: PI PA PG. Wrote the paper: ARAM TLG JA JMFGA MvE. Competing Interests: The authors have declared that no competing interests exist.
ISSN:	1932-6203 1932-6203
DOI:	10.1371/journal.pone.0147208