title: Correction of apolipoprotein A-I-mediated lipid efflux and high density lipoprotein particle formation in human Niemann-Pick type C disease fibroblasts.
abstract: Impaired cell cholesterol trafficking in Niemann-Pick type C (NPC) disease results in the first known instance of impaired regulation of the ATP-binding cassette transporter A1 (ABCA1), a lipid transporter mediating the rate-limiting step in high density lipoprotein (HDL) formation, as a cause of low plasma HDL-cholesterol in humans. We show here that treatment of human NPC1(-/-) fibroblasts with the liver X receptor (LXR) agonist TO-901317 increases ABCA1 expression and activity in human NPC1(-/-) fibroblasts, as indicated by near normalization of efflux of radiolabeled phosphatidylcholine and a marked increase in efflux of cholesterol mass to apoA-I. LXR agonist treatment prior to and during apoA-I incubation resulted in reduction in filipin staining of unesterified cholesterol in late endosomes/lysosomes, as well as cholesterol mass, in NPC1(-/-) cells. HDL species in human NPC disease plasma showed the same pattern of diminished large, cholesterol-rich alpha-1 HDL particles as seen in isolated heterozygous ABCA1 deficiency. Incubating NPC1(-/-) fibroblasts with the LXR agonist normalized the pattern of HDL particle formation by these cells. ABCG1, another LXR target gene involved in cholesterol efflux to HDL, also showed diminished expression in NPC1(-/-) fibroblasts and increased expression upon LXR agonist treatment. These results suggest that NPC1 mutations can be largely bypassed and that NPC1 protein function is non-essential for the trafficking and removal of cellular cholesterol if the down-stream defects in ABCA1 and ABCG1 regulation in NPC disease cells are corrected using an LXR agonist.
authors.affiliation: Department of Medicine, University of Alberta, Edmonton, Alberta T6G 2S2, Canada.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Boadu
authors.forename: Hong Y
authors.initials: HY
authors.lastname: Choi
authors.forename: Diana W K
authors.initials: DW
authors.lastname: Lee
authors.forename: Emma I
authors.initials: EI
authors.lastname: Waddington
authors.forename: Teddy
authors.initials: T
authors.lastname: Chan
authors.forename: Bela
authors.initials: B
authors.lastname: Asztalos
authors.forename: Jean E
authors.initials: JE
authors.lastname: Vance
authors.forename: Alicia
authors.initials: A
authors.lastname: Chan
authors.forename: Graciela
authors.initials: G
authors.lastname: Castro
authors.forename: Gordon A
authors.initials: GA
authors.lastname: Francis
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters / Q000502:physiology; D000255:Adenosine Triphosphate / Q000737:chemistry; D016632:Apolipoprotein A-I / Q000378:metabolism / Q000502:physiology*; D015153:Blotting, Western; D002352:Carrier Proteins / Q000502:physiology; D002460:Cell Line; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008055:Lipids / Q000737:chemistry*; D008074:Lipoproteins / Q000737:chemistry; D008075:Lipoproteins, HDL / Q000737:chemistry*; D008562:Membrane Glycoproteins / Q000502:physiology; D009154:Mutation; D000077296:Niemann-Pick C1 Protein; D009542:Niemann-Pick Diseases / Q000378:metabolism*; D010713:Phosphatidylcholines / Q000737:chemistry
chemical_list: C577836:ABCA1 protein, human; C419353:ABCG1 protein, human; D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters; D016632:Apolipoprotein A-I; D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008055:Lipids; D008074:Lipoproteins; D008075:Lipoproteins, HDL; D008562:Membrane Glycoproteins; C106881:NPC1 protein, human; D000077296:Niemann-Pick C1 Protein; D010713:Phosphatidylcholines; D000255:Adenosine Triphosphate; D002784:Cholesterol