Glycosphingolipid accumulation inhibits cholesterol efflux via the ABCA1/apolipoprotein A-I pathway: 1-phenyl-2-decanoylamino-3-morpholino-1-propanol is a novel cholesterol efflux accelerator.
Cellular glycosphingolipid (GSL) storage is known to promote cholesterol accumulation. Although physical interactions between GSLs and cholesterol are thought to cause intracellular cholesterol "trapping," it is not known whether cholesterol homeostatic mechanisms are also impaired under these conditions. ApoA-I-mediated cholesterol efflux via ABCA1 (ATP-binding cassette transporter A1) is a key regulator of cellular cholesterol balance. Here, we show that apoA-I-mediated cholesterol efflux was inhibited (by up to 53% over 8 h) when fibroblasts were treated with lactosylceramide or the glucocerebrosidase inhibitor conduritol B epoxide. Furthermore, apoA-I-mediated cholesterol efflux from fibroblasts derived from patients with genetic GSL storage diseases (Fabry disease, Sandhoff disease, and GM1 gangliosidosis) was impaired compared with control cells. Conversely, apoA-I-mediated cholesterol efflux from fibroblasts and cholesterol-loaded macrophage foam cells was dose-dependently stimulated (by up to 6-fold over 8 h) by the GSL synthesis inhibitor 1-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP). Unexpectedly, a structurally unrelated GSL synthesis inhibitor, N-butyldeoxynojirimycin, was unable to stimulate apoA-I-mediated cholesterol efflux despite achieving similar GSL depletion. PDMP was found to up-regulate ABCA1 mRNA and protein expression, thereby identifying a contributing mechanism for the observed acceleration of cholesterol efflux to apoA-I. This study reveals a novel defect in cellular cholesterol homeostasis induced by GSL storage and identifies PDMP as a new agent for enhancing cholesterol efflux via the ABCA1/apoA-I pathway.
Glaros
Elias N
EN
Centre for Vascular Research, University of New South Wales, Sydney, New South Wales 2052, Australia.
Kim
Woojin Scott
WS
Quinn
Carmel M
CM
Wong
Jenny
J
Gelissen
Ingrid
I
Jessup
Wendy
W
Garner
Brett
B
D017485:1-Deoxynojirimycin / Q000031:analogs & derivatives* / Q000494:pharmacology; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000737:chemistry*; D015703:Antigens, CD / Q000378:metabolism; D016632:Apolipoprotein A-I / Q000737:chemistry*; D019921:Biotinylation; D015153:Blotting, Western; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005347:Fibroblasts / Q000378:metabolism; D006028:Glycosphingolipids / Q000378:metabolism*; D006801:Humans; D007790:Lactosylceramides / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000737:chemistry; D009000:Monocytes / Q000378:metabolism; D009025:Morpholines / Q000737:chemistry / Q000494:pharmacology; D010743:Phospholipids / Q000737:chemistry; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D015854:Up-Regulation
C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D015703:Antigens, CD; D016632:Apolipoprotein A-I; D004791:Enzyme Inhibitors; D006028:Glycosphingolipids; D007790:Lactosylceramides; D008077:Lipoproteins, LDL; D009025:Morpholines; D010743:Phospholipids; D012333:RNA, Messenger; D017485:1-Deoxynojirimycin; C009744:CDw17 antigen; C033110:RV 538; D002784:Cholesterol; C059896:miglustat