title: Oral D-4F causes formation of pre-beta high-density lipoprotein and improves high-density lipoprotein-mediated cholesterol efflux and reverse cholesterol transport from macrophages in apolipoprotein E-null mice.
abstract: BACKGROUND
  These studies were designed to determine the mechanism of action of an oral apolipoprotein (apo) A-I mimetic peptide, D-4F, which previously was shown to dramatically reduce atherosclerosis in mice.
  
  
  RESULTS
  Twenty minutes after 500 microg of D-4F was given orally to apoE-null mice, small cholesterol-containing particles (CCPs) of 7 to 8 nm with pre-beta mobility and enriched in apoA-I and paraoxonase activity were found in plasma. Before D-4F, both mature HDL and the fast protein liquid chromatography fractions containing the CCPs were proinflammatory. Twenty minutes after oral D-4F, HDL and CCPs became antiinflammatory, and there was an increase in HDL-mediated cholesterol efflux from macrophages in vitro. Oral D-4F also promoted reverse cholesterol transport from intraperitoneally injected cholesterol-loaded macrophages in vivo. In addition, oral D-4F significantly reduced lipoprotein lipid hydroperoxides (LOOH), except for pre-beta HDL fractions, in which LOOH increased.
  
  
  CONCLUSIONS
  The mechanism of action of oral D-4F in apoE-null mice involves rapid formation of CCPs, with pre-beta mobility enriched in apoA-I and paraoxonase activity. As a result, lipoprotein LOOH are reduced, HDL becomes antiinflammatory, and HDL-mediated cholesterol efflux and reverse cholesterol transport from macrophages are stimulated.
authors.affiliation: Division of Cardiology, Department of Medicine, David Geffen School of Medicine at University of California, Los Angeles, 10833 Le Conte Ave, Los Angeles, CA 90095-1679, USA. mnavab@mednet.ucla.edu
authors.forename: Mohamad
authors.initials: M
authors.lastname: Navab
authors.forename: G M
authors.initials: GM
authors.lastname: Anantharamaiah
authors.forename: Srinivasa T
authors.initials: ST
authors.lastname: Reddy
authors.forename: Susan
authors.initials: S
authors.lastname: Hama
authors.forename: Greg
authors.initials: G
authors.lastname: Hough
authors.forename: Victor R
authors.initials: VR
authors.lastname: Grijalva
authors.forename: Alan C
authors.initials: AC
authors.lastname: Wagner
authors.forename: Joy S
authors.initials: JS
authors.lastname: Frank
authors.forename: Geeta
authors.initials: G
authors.lastname: Datta
authors.forename: David
authors.initials: D
authors.lastname: Garber
authors.forename: Alan M
authors.initials: AM
authors.lastname: Fogelman
mesh_terms: D000284:Administration, Oral; D000595:Amino Acid Sequence; D000818:Animals; D016632:Apolipoprotein A-I / Q000494:pharmacology* / Q000627:therapeutic use; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D001161:Arteriosclerosis / Q000097:blood / Q000235:genetics*; D043303:Aryldialkylphosphatase / Q000097:blood; D001692:Biological Transport / Q000187:drug effects; D002478:Cells, Cultured; D002633:Chemotaxis / Q000187:drug effects; D002784:Cholesterol / Q000378:metabolism*; D018920:Coculture Techniques; D004353:Drug Evaluation, Preclinical; D005260:Female; D053442:High-Density Lipoproteins, Pre-beta; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000097:blood / Q000235:genetics*; D007249:Inflammation; D015227:Lipid Peroxidation / Q000187:drug effects; D008075:Lipoproteins, HDL / Q000096:biosynthesis* / Q000097:blood; D017737:Macrophages, Peritoneal / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009000:Monocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism
chemical_list: D016632:Apolipoprotein A-I; D001057:Apolipoproteins E; C465468:D-4F peptide; D053442:High-Density Lipoproteins, Pre-beta; D008075:Lipoproteins, HDL; D002784:Cholesterol; D043303:Aryldialkylphosphatase