title: Gpnmb Is a Potential Marker for the Visceral Pathology in Niemann-Pick Type C Disease.
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.
authors.affiliation: Department of Medical Biochemistry, Academic Medical Center, 1105 AZ, Amsterdam, The Netherlands.
authors.forename: André R A
authors.initials: AR
authors.lastname: Marques
authors.affiliation: Department of Medical Biochemistry, Academic Medical Center, 1105 AZ, Amsterdam, The Netherlands.
authors.forename: Tanit L
authors.initials: TL
authors.lastname: Gabriel
authors.affiliation: Department of Pathology, Academic Medical Center, 1105 AZ, Amsterdam, The Netherlands.
authors.forename: Jan
authors.initials: J
authors.lastname: Aten
authors.affiliation: Department of Medical Biochemistry, Academic Medical Center, 1105 AZ, Amsterdam, The Netherlands.
authors.forename: Cindy P A A
authors.initials: CP
authors.lastname: van Roomen
authors.affiliation: Department of Medical Biochemistry, Academic Medical Center, 1105 AZ, Amsterdam, The Netherlands.
authors.forename: Roelof
authors.initials: R
authors.lastname: Ottenhoff
authors.affiliation: Department of Pathology, Academic Medical Center, 1105 AZ, Amsterdam, The Netherlands.
authors.forename: Nike
authors.initials: N
authors.lastname: Claessen
authors.affiliation: Centro de Investigación Biomédica en Red de Enfermedades Raras, Unidad de Investigación Traslacional, Zaragoza, Spain.
authors.forename: Pilar
authors.initials: P
authors.lastname: Alfonso
authors.affiliation: Centro de Investigación Biomédica en Red de Enfermedades Raras, Unidad de Investigación Traslacional, Zaragoza, Spain.
authors.forename: Pilar
authors.initials: P
authors.lastname: Irún
authors.affiliation: Centro de Investigación Biomédica en Red de Enfermedades Raras, Unidad de Investigación Traslacional, Zaragoza, Spain.
authors.forename: Pilar
authors.initials: P
authors.lastname: Giraldo
authors.affiliation: Department of Medical Biochemistry, Academic Medical Center, 1105 AZ, Amsterdam, The Netherlands.|Department of Biochemistry, Leiden Institute of Chemistry, Leiden University, 2300 RA, Leiden, The Netherlands.
authors.forename: Johannes M F G
authors.initials: JM
authors.lastname: Aerts
authors.affiliation: Department of Medical Biochemistry, Academic Medical Center, 1105 AZ, Amsterdam, The Netherlands.|Department of Biochemistry, Leiden Institute of Chemistry, Leiden University, 2300 RA, Leiden, The Netherlands.
authors.forename: Marco
authors.initials: M
authors.lastname: van Eijk
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D015415:Biomarkers / Q000378:metabolism*; D002460:Cell Line; D002784:Cholesterol / Q000378:metabolism; D004195:Disease Models, Animal; D005136:Eye Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005487:Foam Cells / Q000378:metabolism; D006028:Glycosphingolipids / Q000378:metabolism; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008875:Middle Aged; D052556:Niemann-Pick Disease, Type C / Q000235:genetics / Q000378:metabolism*; D055815:Young Adult
chemical_list: D015415:Biomarkers; D005136:Eye Proteins; C503042:GPNMB protein, human; D006028:Glycosphingolipids; C445671:Gpnmb protein, mouse; D008562:Membrane Glycoproteins; D002784:Cholesterol