An apolipoprotein E synthetic peptide targets to lipoproteins in plasma and mediates both cellular lipoprotein interactions in vitro and acute clearance of cholesterol-rich lipoproteins in vivo.
Apolipoprotein (apo) E mediates lipoprotein binding to cellular lipoprotein receptors. Previously we reported that a synthetic peptide representing a linear dimeric repeat of amino acids 141-155 binds cellular LDL receptors. To prepare an apoE peptide that bound to both cholesterol-rich lipoproteins and lipoprotein receptors, an NH2-terminal acetylated apoE dimer peptide was synthesized. This acetylated peptide preferentially associated with lipoproteins in plasma, whereas nonacylated peptides were poor lipid binders. Acetylated peptide/LDL complexes (molar ratios of 4-5:1) enhanced the interaction of LDL with cultured human fibroblasts by 7-12-fold. Participation by both receptors and cell surface heparin sulfate proteoglycans was observed. When a preformed peptide/125I-LDL complex was injected intravenously into C57BL/6J apoE-deficient mice, its rate of removal was threefold higher than that of 125I-LDL alone. The liver and the spleen were major tissue distribution sites. Intravenous administration of free acetylated peptide resulted in a 30% reduction in total plasma cholesterol within 3-30 min, which reflected a 40-50% and 20-26% reduction in very low density lipoproteins and intermediate density lipoproteins, respectively. Therefore, this peptide selectively associated with cholesterol-rich lipoproteins and mediated their acute clearance in vivo.
Nikoulin
I R
IR
Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037, USA.
Curtiss
L K
LK
D000818:Animals; D001057:Apolipoproteins E / Q000138:chemical synthesis / Q000378:metabolism* / Q000494:pharmacology; D002784:Cholesterol / Q000378:metabolism*; D002847:Chromatography, Agarose; D004587:Electrophoresis, Agar Gel; D006801:Humans; D008074:Lipoproteins / Q000378:metabolism*; D008077:Lipoproteins, LDL / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D010455:Peptides / Q000138:chemical synthesis / Q000378:metabolism* / Q000494:pharmacology; D014018:Tissue Distribution
D001057:Apolipoproteins E; D008074:Lipoproteins; D008077:Lipoproteins, LDL; D010455:Peptides; C030104:lipoprotein cholesterol; D002784:Cholesterol