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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Veröffentlicht in:PloS one Jg. 11; H. 1; S. e0147208
Hauptverfasser: 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
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Sprache:Englisch
Veröffentlicht: United States Public Library of Science 15.01.2016
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ISSN:1932-6203, 1932-6203
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Abstract 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.
AbstractList 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.
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 Npc1.sup.nih/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.
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 Npc1 nih/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.
Audience Academic
Author Gabriel, Tanit L.
Ottenhoff, Roelof
Irún, Pilar
Claessen, Nike
Alfonso, Pilar
Aten, Jan
Giraldo, Pilar
van Eijk, Marco
van Roomen, Cindy P. A. A.
Marques, André R. A.
Aerts, Johannes M. F. G.
AuthorAffiliation 4 Department of Biochemistry, Leiden Institute of Chemistry, Leiden University, 2300 RA, Leiden, The Netherlands
University Hospital S. Maria della Misericordia, Udine, ITALY
3 Centro de Investigación Biomédica en Red de Enfermedades Raras, Unidad de Investigación Traslacional, Zaragoza, Spain
2 Department of Pathology, Academic Medical Center, 1105 AZ, Amsterdam, The Netherlands
1 Department of Medical Biochemistry, Academic Medical Center, 1105 AZ, Amsterdam, The Netherlands
AuthorAffiliation_xml – name: University Hospital S. Maria della Misericordia, Udine, ITALY
– name: 4 Department of Biochemistry, Leiden Institute of Chemistry, Leiden University, 2300 RA, Leiden, The Netherlands
– name: 2 Department of Pathology, Academic Medical Center, 1105 AZ, Amsterdam, The Netherlands
– name: 3 Centro de Investigación Biomédica en Red de Enfermedades Raras, Unidad de Investigación Traslacional, Zaragoza, Spain
– name: 1 Department of Medical Biochemistry, Academic Medical Center, 1105 AZ, Amsterdam, The Netherlands
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  fullname: van Eijk, Marco
BackLink https://www.ncbi.nlm.nih.gov/pubmed/26771826$$D View this record in MEDLINE/PubMed
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ContentType Journal Article
Copyright COPYRIGHT 2016 Public Library of Science
2016 Marques et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.
2016 Marques et al 2016 Marques et al
Copyright_xml – notice: COPYRIGHT 2016 Public Library of Science
– notice: 2016 Marques et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.
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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.
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RelatedPersons Yang, Cindy
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SubjectTerms 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
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Title Gpnmb Is a Potential Marker for the Visceral Pathology in Niemann-Pick Type C Disease
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http://dx.doi.org/10.1371/journal.pone.0147208
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