title: A Short Synthetic Peptide Mimetic of Apolipoprotein A1 Mediates Cholesterol and Globotriaosylceramide Efflux from Fabry Fibroblasts.
abstract: Fabry disease is an X-linked sphingolipid storage disorder caused by a deficiency of the lysosomal enzyme α-galactosidase A (AGA, EC 3.2.1.22) resulting in the intracellular accumulation of globotriaosylceramide (Gb3). We found that Gb3 storage also correlates with accumulation of endosomal-lysosomal cholesterol in Fabry fibroblasts. This cholesterol accumulation may contribute to the phenotypic pathology of Fabry disease by slowing endosomal-lysosomal trafficking. We found that LDL receptor expression is not downregulated in Fabry fibroblasts resulting in accumulation of both cholesterol and Gb3. 5A-Palmitoyl oleoyl-phosphatidylcholine (5AP) is a phospholipid complex containing a short synthetic peptide that mimics apolipoprotein A1, the main protein component of high-density lipoprotein (HDL) that mediates the efflux of cholesterol from cells via the ATP-binding cassette transporter. We used 5AP and HDL to remove cholesterol from Fabry fibroblasts to examine the fate of accumulated cellular Gb3. Using immunostaining techniques, we found that 5AP is highly effective for depleting cholesterol and Gb3 in these cells. 5AP restores the ApoA-1-mediated cholesterol efflux leading to mobilization of cholesterol and reduction of Gb3 in Fabry fibroblasts.
authors.affiliation: NIDDK, LCBB, National Institutes of Health, Building 8, Room 420, 8 Center Drive, Bethesda, MD, 20892-0851, USA. hoffmanu@niddk.nih.gov.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Schueler
authors.affiliation: NINDS National Institutes of Health, Bethesda, MD, 20892-0851, USA.
authors.forename: Christine
authors.initials: C
authors.lastname: Kaneski
authors.affiliation: NHLBI Lipoprotein Metabolism Section, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Alan
authors.initials: A
authors.lastname: Remaley
authors.affiliation: NHLBI Lipoprotein Metabolism Section, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Stephen
authors.initials: S
authors.lastname: Demosky
authors.affiliation: NIDDK, LCBB, National Institutes of Health, Building 8, Room 420, 8 Center Drive, Bethesda, MD, 20892-0851, USA.
authors.forename: Nancy
authors.initials: N
authors.lastname: Dwyer
authors.affiliation: NIDDK, LCBB, National Institutes of Health, Building 8, Room 420, 8 Center Drive, Bethesda, MD, 20892-0851, USA.
authors.forename: Joan
authors.initials: J
authors.lastname: Blanchette-Mackie
authors.affiliation: NIDDK, LCBB, National Institutes of Health, Building 8, Room 420, 8 Center Drive, Bethesda, MD, 20892-0851, USA.
authors.forename: John
authors.initials: J
authors.lastname: Hanover
authors.affiliation: NINDS National Institutes of Health, Bethesda, MD, 20892-0851, USA.
authors.forename: Roscoe
authors.initials: R
authors.lastname: Brady