Apolipoprotein E derived HDL mimetic peptide ATI-5261 promotes nascent HDL formation and reverse cholesterol transport in vitro

Anouar Hafiane; John K Bielicki; Jan O Johansson; Jacques Genest

doi:10.1016/j.bbalip.2014.07.018

Apolipoprotein E derived HDL mimetic peptide ATI-5261 promotes nascent HDL formation and reverse cholesterol transport in vitro

Biochim Biophys Acta. 2014 Oct;1842(10):1498-512. doi: 10.1016/j.bbalip.2014.07.018. Epub 2014 Aug 1.

Authors

Anouar Hafiane¹, John K Bielicki², Jan O Johansson³, Jacques Genest⁴

Affiliations

¹ Cardiovascular Genetics Laboratory, Cardiology Division, McGill University Health Centre/Royal Victoria Hospital, Montréal, Québec H3A 1A1, Canada.
² Lawrence Berkeley National Laboratory, Donner Laboratory, MS1-267 Berkeley, CA, USA.
³ Artery Therapeutics, San Ramon, CA, USA.
⁴ Cardiovascular Genetics Laboratory, Cardiology Division, McGill University Health Centre/Royal Victoria Hospital, Montréal, Québec H3A 1A1, Canada. Electronic address: jacques.genest@mcgill.ca.

PMID: 25091998
DOI: 10.1016/j.bbalip.2014.07.018

Abstract

Modulation of the reverse cholesterol transport (RCT) pathway may provide a therapeutic target for the prevention and treatment of atherosclerotic cardiovascular disease (CVD). In the present study, we evaluated a novel 26-amino acid apolipoprotein mimetic peptide (ATI-5261) designed from the carboxyl terminal of apoE, in its ability to mimic apoA-I functionality in RCT in vitro. Our data shows that nascent HDL-like (nHDL) particles generated by incubating cells over-expressing ABCA1 with ATI-5261 increase the rate of specific ABCA1 dependent lipid efflux, with high affinity interactions with ABCA1. We also show that these nHDL particles interact with membrane micro-domains in a manner similar to nHDL apoA-I. These nHDL particles then interact with the ABCG1 transporter and are remodeled by plasma HDL-modulating enzymes. Finally, we show that these mature HDL-like particles are taken up by SR-BI for cholesterol delivery to liver cells. This ATI-5621-mediated process mimics apoA-I and may provide a means to prevent cholesterol accumulation in the artery wall. In this study, we propose an integrative physiology approach of HDL biogenesis with the synthetic peptide ATI-5261. These experiments provide new insights for potential therapeutic use of apolipoprotein mimetic peptides.

Keywords: ABCA1; ABCG1; Cholesterol efflux; HDL; Reverse cholesterol transport; SR-BI.