Novel Apo E-Derived ABCA1 Agonist Peptide (CS-6253) Promotes Reverse Cholesterol Transport and Induces Formation of preβ-1 HDL In Vitro

PLoS One. 2015 Jul 24;10(7):e0131997. doi: 10.1371/journal.pone.0131997. eCollection 2015.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter 1 / agonists
  • ATP Binding Cassette Transporter 1 / genetics
  • ATP Binding Cassette Transporter 1 / metabolism*
  • Animals
  • Apolipoprotein A-I / metabolism
  • Apolipoproteins E / chemistry
  • Apolipoproteins E / metabolism*
  • Biological Transport / drug effects
  • CD36 Antigens / metabolism
  • Cell Line
  • Cell Line, Tumor
  • Cholesterol / metabolism*
  • Dose-Response Relationship, Drug
  • Foam Cells / metabolism
  • High-Density Lipoproteins, Pre-beta / metabolism*
  • Humans
  • Intercellular Signaling Peptides and Proteins
  • Macrophages / metabolism
  • Male
  • Mice, Inbred C57BL
  • Peptides / metabolism
  • Peptides / pharmacology*
  • Phospholipids / metabolism
  • Rats
  • Time Factors


  • ATI-5261
  • ATP Binding Cassette Transporter 1
  • Apolipoprotein A-I
  • Apolipoproteins E
  • CD36 Antigens
  • CS-6253
  • High-Density Lipoproteins, Pre-beta
  • Intercellular Signaling Peptides and Proteins
  • Peptides
  • Phospholipids
  • Cholesterol