title: Caveolin-1-mediated apolipoprotein A-I membrane binding sites are not required for cholesterol efflux.
abstract: Caveolin-1 (Cav1), a structural protein required for the formation of invaginated membrane domains known as caveolae, has been implicated in cholesterol trafficking and homeostasis. Here we investigated the contribution of Cav1 to apolipoprotein A-I (apoA-I) cell surface binding and intracellular processing using mouse embryonic fibroblasts (MEFs) derived from wild type (WT) or Cav1-deficient (Cav1(-/-)) animals. We found that cells expressing Cav1 have 2.6-fold more apoA-I binding sites than Cav1(-/-) cells although these additional binding sites are not associated with detergent-free lipid rafts. Further, Cav1-mediated binding targets apoA-I for internalization and degradation and these processes are not correlated to cholesterol efflux. Despite lower apoA-I binding, cholesterol efflux from Cav1(-/-) MEFs is 1.7-fold higher than from WT MEFs. Stimulation of ABCA1 expression with an LXR agonist enhances cholesterol efflux from both WT and Cav1(-/-) cells without increasing apoA-I surface binding or affecting apoA-I processing. Our results indicate that there are at least two independent lipid binding sites for apoA-I; Cav1-mediated apoA-I surface binding and uptake is not linked to cholesterol efflux, indicating that membrane domains other than caveolae regulate ABCA1-mediated cholesterol efflux.
authors.affiliation: Centre de Recherche des Cordeliers, INSERM, U872, Paris, France.
authors.forename: Soazig
authors.initials: S
authors.lastname: Le Lay
authors.forename: Macarena
authors.initials: M
authors.lastname: Rodriguez
authors.forename: Wendy
authors.initials: W
authors.lastname: Jessup
authors.forename: Carles
authors.initials: C
authors.lastname: Rentero
authors.forename: Qiong
authors.initials: Q
authors.lastname: Li
authors.forename: Siân
authors.initials: S
authors.lastname: Cartland
authors.forename: Thomas
authors.initials: T
authors.lastname: Grewal
authors.forename: Katharina
authors.initials: K
authors.lastname: Gaus
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000465:Algorithms; D000818:Animals; D016632:Apolipoprotein A-I / Q000378:metabolism*; D001665:Binding Sites; D001667:Binding, Competitive; D001692:Biological Transport; D015153:Blotting, Western; D051242:Caveolin 1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism*; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism*; D004622:Embryo, Mammalian / Q000166:cytology; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006845:Hydrocarbons, Fluorinated / Q000494:pharmacology; D007700:Kinetics; D000071518:Liver X Receptors; D021962:Membrane Microdomains / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D057093:Orphan Nuclear Receptors / Q000819:agonists; D011485:Protein Binding; D013449:Sulfonamides / Q000494:pharmacology; D013696:Temperature; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
chemical_list: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D016632:Apolipoprotein A-I; D051242:Caveolin 1; D002784:Cholesterol; D006845:Hydrocarbons, Fluorinated; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D013449:Sulfonamides; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides