d-4f-peptide and Hyperlipoproteinemia-Type-II

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.. 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.. 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.

Topics: Administration, Oral; Amino Acid Sequence; Animals; Apolipoprotein A-I; Apolipoproteins E; Arteriosclerosis; Aryldialkylphosphatase; Biological Transport; Cells, Cultured; Chemotaxis; Cholesterol; Coculture Techniques; Drug Evaluation, Preclinical; Female; High-Density Lipoproteins, Pre-beta; Humans; Hyperlipoproteinemia Type II; Inflammation; Lipid Peroxidation; Lipoproteins, HDL; Macrophages, Peritoneal; Mice; Mice, Inbred C57BL; Mice, Knockout; Molecular Sequence Data; Monocytes