title: An apoA-I mimetic peptibody generates HDL-like particles and increases alpha-1 HDL subfraction in mice.
abstract: The aim of this study is to investigate the capability of an apoA-I mimetic with multiple amphipathic helices to form HDL-like particles in vitro and in vivo. To generate multivalent helices and to track the peptide mimetic, we have constructed a peptibody by fusing two tandem repeats of 4F peptide to the C terminus of a murine IgG Fc fragment. The resultant peptidbody, mFc-2X4F, dose-dependently promoted cholesterol efflux in vitro, and the efflux potency was superior to monomeric 4F peptide. Like apoA-I, mFc-2X4F stabilized ABCA1 in J774A.1 and THP1 cells. The peptibody formed larger HDL particles when incubated with cultured cells compared with those by apoA-I. Interestingly, when administered to mice, mFc-2X4F increased both pre-β and α-1 HDL subfractions. The lipid-bound mFc-2X4F was mostly in the α-1 migrating subfraction. Most importantly, mFc-2X4F and apoA-I were found to coexist in the same HDL particles formed in vivo. These data suggest that the apoA-I mimetic peptibody is capable of mimicking apoA-I to generate HDL particles. The peptibody and apoA-I may work cooperatively to generate larger HDL particles in vivo, either at the cholesterol efflux stage and/or via fusion of HDL particles that were generated by the peptibody and apoA-I individually.
authors.affiliation: Department of Metabolic Disorders, Amgen, Inc., Thousand Oaks, CA 91320, USA.
authors.forename: Shu-Chen
authors.initials: SC
authors.lastname: Lu
authors.forename: Larissa
authors.initials: L
authors.lastname: Atangan
authors.forename: Ki
authors.initials: K
authors.lastname: Won Kim
authors.forename: Michelle M
authors.initials: MM
authors.lastname: Chen
authors.forename: Renee
authors.initials: R
authors.lastname: Komorowski
authors.forename: Carolyn
authors.initials: C
authors.lastname: Chu
authors.forename: Joon
authors.initials: J
authors.lastname: Han
authors.forename: Sylvia
authors.initials: S
authors.lastname: Hu
authors.forename: Wei
authors.initials: W
authors.lastname: Gu
authors.forename: Murielle
authors.initials: M
authors.lastname: Véniant
authors.forename: Minghan
authors.initials: M
authors.lastname: Wang
mesh_terms: D016475:3T3 Cells; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000737:chemistry; D000595:Amino Acid Sequence; D000818:Animals; D016632:Apolipoprotein A-I / Q000737:chemistry / Q000494:pharmacology*; D002784:Cholesterol / Q000097:blood; D004305:Dose-Response Relationship, Drug; D057809:HEK293 Cells; D056945:Hep G2 Cells; D053442:High-Density Lipoproteins, Pre-beta / Q000737:chemistry; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000737:chemistry; D008075:Lipoproteins, HDL / Q000097:blood; D008264:Macrophages / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D010455:Peptides / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D055550:Protein Stability; D017433:Protein Structure, Secondary; D011993:Recombinant Fusion Proteins / Q000737:chemistry* / Q000494:pharmacology; D020080:Tandem Repeat Sequences
chemical_list: C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D016632:Apolipoprotein A-I; D053442:High-Density Lipoproteins, Pre-beta; D007141:Immunoglobulin Fc Fragments; D008075:Lipoproteins, HDL; D010455:Peptides; D011993:Recombinant Fusion Proteins; C035392:high density lipoprotein-1; D002784:Cholesterol