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Effect of an arginine-rich amphipathic helical peptide on plasma cholesterol in dyslipidemic mice

  • David W Garber
    Correspondence
    Corresponding author. Tel.: +1-205-934-1218; fax: +1-205-975-8079
    Affiliations
    Departments of Medicine, Biochemistry and Molecular Genetics, and the Atherosclerosis Research Unit, The University of Alabama at Birmingham, BDB Room D-654, 1530 3rd Ave S., Birmingham, AL 35294-0012, USA
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  • Shaila Handattu
    Affiliations
    Departments of Medicine, Biochemistry and Molecular Genetics, and the Atherosclerosis Research Unit, The University of Alabama at Birmingham, BDB Room D-654, 1530 3rd Ave S., Birmingham, AL 35294-0012, USA
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  • Ibrahim Aslan
    Affiliations
    Departments of Medicine, Biochemistry and Molecular Genetics, and the Atherosclerosis Research Unit, The University of Alabama at Birmingham, BDB Room D-654, 1530 3rd Ave S., Birmingham, AL 35294-0012, USA
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  • Geeta Datta
    Affiliations
    Departments of Medicine, Biochemistry and Molecular Genetics, and the Atherosclerosis Research Unit, The University of Alabama at Birmingham, BDB Room D-654, 1530 3rd Ave S., Birmingham, AL 35294-0012, USA
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  • Manjula Chaddha
    Affiliations
    Departments of Medicine, Biochemistry and Molecular Genetics, and the Atherosclerosis Research Unit, The University of Alabama at Birmingham, BDB Room D-654, 1530 3rd Ave S., Birmingham, AL 35294-0012, USA
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  • G.M Anantharamaiah
    Affiliations
    Departments of Medicine, Biochemistry and Molecular Genetics, and the Atherosclerosis Research Unit, The University of Alabama at Birmingham, BDB Room D-654, 1530 3rd Ave S., Birmingham, AL 35294-0012, USA
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      Abstract

      We have shown that the dual domain peptide Ac-hE18A-NH2, in which LRKLRKRLLR, (141–150 region of human apo E) covalently linked to a class A lipid-associating domain, is able to associate with apo B-containing lipoproteins and enhance their clearance both in vitro and in vivo. We present here the differential effects of this peptide on the plasma cholesterol levels in different mouse models. The peptide intravenously administered (100 μg) into C57BL/6J mice on atherogenic diet, apo E null, and apo E null/LDL-receptor (LDL-R) null double knock out mouse models, was able to rapidly reduce plasma cholesterol levels within 2 min, and the effect persisted for more than 6 h. The reduction was limited to the VLDL and IDL/LDL fractions; HDL was not reduced in any mouse model studied. However, the peptide had no effect on the plasma cholesterol levels in C57BL/6J mice on normal diet, LDL-R null mice on normal chow, and LDL-R null mice on Western diet. Administration to LDL-R null mice of 125I-labelled human lipoproteins incubated with peptide resulted in accelerated human VLDL and LDL clearance with associated increase of radioactivity in the liver. These results, coupled with our earlier in vitro observations, indicate that the Arg-rich peptide-assisted rapid clearance of plasma cholesterol in dyslipidemic mice is due to the peptide targeting apo B-48-containing atherogenic lipoproteins to the liver for increased uptake and degradation.

      Keywords

      Abbreviations:

      Apo, apolipoprotein (), VLDL, very low density lipoprotein (), IDL, intermediate density lipoprotein (), LDL, low density lipoprotein (), HDL, high density lipoprotein (), LDL-R, low density lipoprotein receptor (), Arg, arginine (), LRP, LDL-receptor-related protein (), LPL, lipoprotein lipase (), HSPG, heparan sulfate proteoglycan (), PBS, phosphate-buffered saline (), EDTA, ethylenediaminetetraacetic acid (), SDS, sodium dodecyl sulfate (), PAGE, polyacrylamide gel electrophoresis (), CLiP, column lipoprotein profiles ()
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