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Title: Novel apo E-derived ABCA1 agonist peptide (CS-6253) promotes reverse cholesterol transport and induces formation of preβ-1 HDL in vitro

Abstract

Apolipoprotein (apo) mimetic peptides replicate some aspects of HDL function. We have previously reported the effects of compound ATI-5261 on its ability to replicate many functions of native apo A-I in the process of HDL biogenesis. ATI-5261 induced muscle toxicity in wild type C57Bl/6 mice, increased CPK, ALT and AST and increase in triglyceride (Tg) levels. Aromatic phenylalanine residues on the non-polar face of ATI-5261, together with positively charged arginine residues at the lipid-water interface were responsible for these effects. This information was used to create a novel analog (CS-6253) that was non-toxic. We evaluated this peptide designed from the carboxyl terminus of apo E, in its ability to mimic apo A-I functionality. Our data shows that the lipidated particles generated by incubating cells overexpressing ABCA1 with lipid free CS-6253 enhances the rate of ABCA1 lipid efflux with high affinity interactions with native ABCA1 oligomeric forms and plasma membrane micro-domains. Interaction between ABCA1 and lipid free CS-6253 resulted in formation of nascent HDL-CS-6253 particles that are actively remodeled in plasma. Mature HDL-CS-6253 particles deliver cholesterol to liver cells via SR-BI in-vitro. CS-6253 significantly increases cholesterol efflux in murine macrophages and in human THP-1 macrophage-derived foam cells expressing ABCA1. Addition ofmore » CS-6253 to plasma dose-dependently displaced apo A-I from α-HDL particles and led to de novo formation of preβ-1 HDL that stimulates ABCA1 dependent cholesterol efflux efficiently. When incubated with human plasma CS-6253 was also found to bind with HDL and LDL and promoted the transfer of cholesterol from HDL to LDL predominantly. Our data shows that CS-6253 mimics apo A-I in its ability to promote ABCA1-mediated formation of nascent HDL particles, and enhances formation of preβ-1 HDL with increase in the cycling of apo A-I between the preβ and α-HDL particles in-vitro. These mechanisms are potentially anti-atherogenic.« less

Authors:
 [1];  [2];  [3];  [1];  [4]
+ Show Author Affiliations
  1. Research Inst. of the McGill Univ. Health Centre, Montreal, Quebec (Canada). Cardiovascular Research Laboratories Lab.
  2. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Donner Lab.
  3. Artery Therapeutics, San Ramon, CA (United States)
  4. Wake Forest School of Medicine, Winston-Salem, NC (United States)
Publication Date:
Research Org.:
Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)
Sponsoring Org.:
USDOE; Canadian Institutes of Health Research (CIHR)
OSTI Identifier:
1212421
Grant/Contract Number:  
AC02-05CH11231
Resource Type:
Accepted Manuscript
Journal Name:
PLoS ONE
Additional Journal Information:
Journal Volume: 10; Journal Issue: 7; Journal ID: ISSN 1932-6203
Publisher:
Public Library of Science
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; cholesterol; lipids; blood plasma; BHK cells; macrophages; lipoproteins; phospholipids; apolipoproteins

Citation Formats

Hafiane, Anouar, Bielicki, John K., Johansson, Jan O., Genest, Jacques, and Zhu, Xuewei. Novel apo E-derived ABCA1 agonist peptide (CS-6253) promotes reverse cholesterol transport and induces formation of preβ-1 HDL in vitro. United States: N. p., 2015. Web. doi:10.1371/journal.pone.0131997.
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Hafiane, Anouar, Bielicki, John K., Johansson, Jan O., Genest, Jacques, & Zhu, Xuewei. Novel apo E-derived ABCA1 agonist peptide (CS-6253) promotes reverse cholesterol transport and induces formation of preβ-1 HDL in vitro. United States. https://doi.org/10.1371/journal.pone.0131997
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Hafiane, Anouar, Bielicki, John K., Johansson, Jan O., Genest, Jacques, and Zhu, Xuewei. Fri . "Novel apo E-derived ABCA1 agonist peptide (CS-6253) promotes reverse cholesterol transport and induces formation of preβ-1 HDL in vitro". United States. https://doi.org/10.1371/journal.pone.0131997. https://www.osti.gov/servlets/purl/1212421.
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@article{osti_1212421,
title = {Novel apo E-derived ABCA1 agonist peptide (CS-6253) promotes reverse cholesterol transport and induces formation of preβ-1 HDL in vitro},
author = {Hafiane, Anouar and Bielicki, John K. and Johansson, Jan O. and Genest, Jacques and Zhu, Xuewei},
abstractNote = {Apolipoprotein (apo) mimetic peptides replicate some aspects of HDL function. We have previously reported the effects of compound ATI-5261 on its ability to replicate many functions of native apo A-I in the process of HDL biogenesis. ATI-5261 induced muscle toxicity in wild type C57Bl/6 mice, increased CPK, ALT and AST and increase in triglyceride (Tg) levels. Aromatic phenylalanine residues on the non-polar face of ATI-5261, together with positively charged arginine residues at the lipid-water interface were responsible for these effects. This information was used to create a novel analog (CS-6253) that was non-toxic. We evaluated this peptide designed from the carboxyl terminus of apo E, in its ability to mimic apo A-I functionality. Our data shows that the lipidated particles generated by incubating cells overexpressing ABCA1 with lipid free CS-6253 enhances the rate of ABCA1 lipid efflux with high affinity interactions with native ABCA1 oligomeric forms and plasma membrane micro-domains. Interaction between ABCA1 and lipid free CS-6253 resulted in formation of nascent HDL-CS-6253 particles that are actively remodeled in plasma. Mature HDL-CS-6253 particles deliver cholesterol to liver cells via SR-BI in-vitro. CS-6253 significantly increases cholesterol efflux in murine macrophages and in human THP-1 macrophage-derived foam cells expressing ABCA1. Addition of CS-6253 to plasma dose-dependently displaced apo A-I from α-HDL particles and led to de novo formation of preβ-1 HDL that stimulates ABCA1 dependent cholesterol efflux efficiently. When incubated with human plasma CS-6253 was also found to bind with HDL and LDL and promoted the transfer of cholesterol from HDL to LDL predominantly. Our data shows that CS-6253 mimics apo A-I in its ability to promote ABCA1-mediated formation of nascent HDL particles, and enhances formation of preβ-1 HDL with increase in the cycling of apo A-I between the preβ and α-HDL particles in-vitro. These mechanisms are potentially anti-atherogenic.},
doi = {10.1371/journal.pone.0131997},
journal = {PLoS ONE},
number = 7,
volume = 10,
place = {United States},
year = {Fri Jul 24 00:00:00 EDT 2015},
month = {Fri Jul 24 00:00:00 EDT 2015}
}
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https://doi.org/10.1371/journal.pone.0131997
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Cholesterol Efflux Capacity, Carotid Atherosclerosis, and Cerebrovascular Symptomatology
journal, April 2014

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  • Arteriosclerosis, Thrombosis, and Vascular Biology, Vol. 34, Issue 4
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Phosphorylation and Stabilization of ATP Binding Cassette Transporter A1 by Synthetic Amphiphilic Helical Peptides
journal, December 2003

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  • Journal of Biological Chemistry, Vol. 279, Issue 8
  • DOI: 10.1074/jbc.C300553200

Macrophage apoAI protects against dyslipidemia-induced dermatitis and atherosclerosis without affecting HDL
journal, March 2015

  • Tavori, Hagai; Su, Yan Ru; Yancey, Patricia G.
  • Journal of Lipid Research, Vol. 56, Issue 3
  • DOI: 10.1194/jlr.m056408

cDNA cloning of human apoA-I: Amino acid sequence of preproapoA-I
journal, April 1983

  • Law, Simon W.; Gray, Glenn; Brewer, H. Bryan
  • Biochemical and Biophysical Research Communications, Vol. 112, Issue 1
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Protein Measurement with the Folin Phenol Reagent
journal, November 1951

Sterol synthesis is up-regulated in cholesterol-loaded pigeon macrophages during induction of cholesterol efflux
journal, October 1999

Apolipoprotein-mediated removal of cellular cholesterol and phospholipids
journal, December 1996

Studies of synthetic peptide analogs of the amphipathic helix. Structure of complexes with dimyristoyl phosphatidylcholine.
journal, August 1985

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