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Vienken, Hans; Mabrouki, Nathalie; Grabau, Katja; Claas, Ralf Frederik; Rudowski, Agnes; Schömel, Nina; Pfeilschifter, Josef; Lütjohann, Dieter; van Echten-Deckert, Gerhild; Meyer zu Heringdorf, Dagmar

Characterization of cholesterol homeostasis in sphingosine-1-phosphate lyase-deficient fibroblasts reveals a Niemann-Pick disease type C-like phenotype with enhanced lysosomal Ca2+ storage

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  • Medientyp: E-Artikel
  • Titel: Characterization of cholesterol homeostasis in sphingosine-1-phosphate lyase-deficient fibroblasts reveals a Niemann-Pick disease type C-like phenotype with enhanced lysosomal Ca2+ storage
  • Beteiligte: Vienken, Hans; Mabrouki, Nathalie; Grabau, Katja; Claas, Ralf Frederik; Rudowski, Agnes; Schömel, Nina; Pfeilschifter, Josef; Lütjohann, Dieter; van Echten-Deckert, Gerhild; Meyer zu Heringdorf, Dagmar
  • Erschienen: Springer Science and Business Media LLC, 2017
  • Erschienen in: Scientific Reports
  • Sprache: Englisch
  • DOI: 10.1038/srep43575
  • ISSN: 2045-2322
  • Schlagwörter: Multidisciplinary
  • Entstehung:
  • Anmerkungen:
  • Beschreibung: <jats:title>Abstract</jats:title><jats:p>Sphingosine-1-phosphate (S1P) lyase irreversibly cleaves S1P, thereby catalysing the ultimate step of sphingolipid degradation. We show here that embryonic fibroblasts from S1P lyase-deficient mice (<jats:italic>Sgpl1</jats:italic><jats:sup>−/−</jats:sup>-MEFs), in which S1P and sphingosine accumulate, have features of Niemann-Pick disease type C (NPC) cells. In the presence of serum, overall cholesterol content was elevated in <jats:italic>Sgpl1</jats:italic><jats:sup>−/−</jats:sup>-MEFs, due to upregulation of the LDL receptor and enhanced cholesterol uptake. Despite this, activation of sterol regulatory element-binding protein-2 was increased in <jats:italic>Sgpl1</jats:italic><jats:sup>−/−</jats:sup>-MEFs, indicating a local lack of cholesterol at the ER. Indeed, free cholesterol was retained in NPC1-containing vesicles, which is a hallmark of NPC. Furthermore, upregulation of amyloid precursor protein in <jats:italic>Sgpl1</jats:italic><jats:sup>−/−</jats:sup>-MEFs was mimicked by an NPC1 inhibitor in <jats:italic>Sgpl1</jats:italic><jats:sup>+/+</jats:sup>-MEFs and reduced by overexpression of NPC1. Lysosomal pH was not altered by S1P lyase deficiency, similar to NPC. Interestingly, lysosomal Ca<jats:sup>2+</jats:sup> content and bafilomycin A1-induced [Ca<jats:sup>2+</jats:sup>]<jats:sub>i</jats:sub> increases were enhanced in <jats:italic>Sgpl1</jats:italic><jats:sup>−/−</jats:sup>-MEFs, contrary to NPC. These results show that both a primary defect in cholesterol trafficking and S1P lyase deficiency cause overlapping phenotypic alterations, and challenge the present view on the role of sphingosine in lysosomal Ca<jats:sup>2+</jats:sup> homeostasis.</jats:p>
  • Zugangsstatus: Freier Zugang