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We show here that embryonic fibroblasts from S1P lyase-deficient mice (<jats:italic>Sgpl1<\/jats:italic><jats:sup>\u2212\/\u2212<\/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>\u2212\/\u2212<\/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>\u2212\/\u2212<\/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>\u2212\/\u2212<\/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>\u2212\/\u2212<\/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>","DOI":"10.1038\/srep43575","type":"journal-article","created":{"date-parts":[[2017,3,6]],"date-time":"2017-03-06T10:14:13Z","timestamp":1488795253000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["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"],"prefix":"10.1038","volume":"7","author":[{"given":"Hans","family":"Vienken","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathalie","family":"Mabrouki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katja","family":"Grabau","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ralf Frederik","family":"Claas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agnes","family":"Rudowski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nina","family":"Sch\u00f6mel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Josef","family":"Pfeilschifter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dieter","family":"L\u00fctjohann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerhild","family":"van Echten-Deckert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dagmar","family":"Meyer zu Heringdorf","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2017,3,6]]},"reference":[{"key":"BFsrep43575_CR1","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1016\/j.tcb.2011.09.003","volume":"22","author":"M Maceyka","year":"2012","unstructured":"Maceyka, M., Harikumar, K. 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