Correction of Apolipoprotein A-I-mediated Lipid Efflux and High Density Lipoprotein Particle Formation in Human Niemann-Pick Type C Disease Fibroblasts

摘要: Impaired cell cholesterol trafficking in Niemann-Pick type C (NPC) disease results the first known instance of impaired regulation ATP-binding cassette transporter A1 (ABCA1), a lipid mediating rate-limiting step high density lipoprotein (HDL) formation, as cause low plasma HDL-cholesterol humans. We show here that treatment human NPC1-/- fibroblasts with liver X receptor (LXR) agonist TO-901317 increases ABCA1 expression and activity fibroblasts, indicated by near normalization efflux radiolabeled phosphatidylcholine marked increase mass to apoA-I. LXR prior during apoA-I incubation resulted reduction filipin staining unesterified late endosomes/lysosomes, well mass, cells. HDL species NPC showed same pattern diminished large, cholesterol-rich α-1 particles seen isolated heterozygous deficiency. Incubating normalized particle formation these ABCG1, another target gene involved HDL, also increased upon treatment. These suggest NPC1 mutations can be largely bypassed protein function is non-essential for removal cellular if down-stream defects ABCG1 cells are corrected using an agonist.