Details

Autor(en) / 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

Titel

Characterization of cholesterol homeostasis in sphingosine-1-phosphate lyase-deficient fibroblasts reveals a Niemann-Pick disease type C-like phenotype with enhanced lysosomal Ca 2+ storage

Ist Teil von

• Scientific reports, 2017-03, Vol.7, p.43575

Ort / Verlag

England

Erscheinungsjahr

2017

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• 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 (Sgpl1 -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 Sgpl1 -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 Sgpl1 -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 Sgpl1 -MEFs was mimicked by an NPC1 inhibitor in Sgpl1 -MEFs and reduced by overexpression of NPC1. Lysosomal pH was not altered by S1P lyase deficiency, similar to NPC. Interestingly, lysosomal Ca content and bafilomycin A1-induced [Ca ] increases were enhanced in Sgpl1 -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 homeostasis.