APOA2 increases cholesterol efflux capacity to plasma HDL by displacing the C-terminus of resident APOA1.

Autor:	Sarkar S; Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA, USA., Morris J; Department of Pathology and Laboratory Medicine, University of Cincinnati, Cincinnati, OH, USA., You Y; Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA, USA., Sexmith H; Department of Pediatrics, Cincinnati Children's Hospital Medical Center and the University of Cincinnati, Cincinnati, OH, USA., Street SE; Department of Pathology and Laboratory Medicine, University of Cincinnati, Cincinnati, OH, USA., Thibert SM; Environmental Molecular Sciences Laboratory, Pacific Northwest National Laboratory, Richland, WA, USA., Attah IK; Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA, USA., Hutchinson Bunch CM; Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA, USA., Novikova IV; Environmental Molecular Sciences Laboratory, Pacific Northwest National Laboratory, Richland, WA, USA., Evans JE; Environmental Molecular Sciences Laboratory, Pacific Northwest National Laboratory, Richland, WA, USA., Shah AS; Department of Pediatrics, Cincinnati Children's Hospital Medical Center and the University of Cincinnati, Cincinnati, OH, USA., Gordon SM; Department of Physiology and the Saha Cardiovascular Research Center, University of Kentucky College of Medicine, Lexington, KY, USA., Segrest JP; Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA., Bornfeldt KE; Department of Medicine, UW Medicine Diabetes Institute, University of Washington, Seattle WA, USA., Vaisar T; Department of Medicine, UW Medicine Diabetes Institute, University of Washington, Seattle WA, USA., Heinecke JW; Department of Medicine, UW Medicine Diabetes Institute, University of Washington, Seattle WA, USA., Davidson WS; Department of Pathology and Laboratory Medicine, University of Cincinnati, Cincinnati, OH, USA. Electronic address: sean.davidson@uc.edu., Melchior JT; Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA, USA; Department of Pathology and Laboratory Medicine, University of Cincinnati, Cincinnati, OH, USA; Department of Neurology, Oregon Health and Science University, Portland, OR, USA. Electronic address: john.melchior@pnnl.gov.
Jazyk:	angličtina
Zdroj:	Journal of lipid research [J Lipid Res] 2024 Dec; Vol. 65 (12), pp. 100686. Date of Electronic Publication: 2024 Oct 28.
DOI:	10.1016/j.jlr.2024.100686
Abstrakt:	The ability of high-density lipoprotein (HDL) to promote cellular cholesterol efflux is a more robust predictor of cardiovascular disease protection than HDL-cholesterol levels in plasma. Previously, we found that lipidated HDL containing both apolipoprotein A-I (APOA1) and A-II (APOA2) promotes cholesterol efflux via the ATP-binding cassette transporter (ABCA1). In the current study, we directly added purified, lipid-free APOA2 to human plasma and found a dose-dependent increase in whole plasma cholesterol efflux capacity. APOA2 likewise increased the cholesterol efflux capacity of isolated HDL with the maximum effect occurring when equal masses of APOA1 and APOA2 coexisted on the particles. Follow-up experiments with reconstituted HDL corroborated that the presence of both APOA1 and APOA2 were necessary for the increased efflux. Using limited proteolysis and chemical cross-linking mass spectrometry, we found that APOA2 induced a conformational change in the N- and C-terminal helices of APOA1. Using reconstituted HDL with APOA1 deletion mutants, we further showed that APOA2 lost its ability to stimulate ABCA1 efflux to HDL if the C-terminal domain of APOA1 was absent, but retained this ability when the N-terminal domain was absent. Based on these findings, we propose a model in which APOA2 displaces the C-terminal helix of APOA1 from the HDL surface which can then interact with ABCA1-much like it does in lipid-poor APOA1. These findings suggest APOA2 may be a novel therapeutic target given this ability to open a large, high-capacity pool of HDL particles to enhance ABCA1-mediated cholesterol efflux. Competing Interests: Conflicts of Interests The authors declare that they have no conflicts of interests with the contents of this article. (Published by Elsevier Inc.)
Databáze:	MEDLINE
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