on May 17, 2007
Published online before print May 17, 2007, doi: 10.1161/ATVBAHA.107.142455
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Submitted on February 19, 2007
Accepted on May 7, 2007
Minimal Lipidation of Pre-
HDL by ABCA1 Results in Reduced Ability to Interact with ABCA1
Anny Mulya ;
From the Departments of Pathology/Section on Lipid Sciences (A.M., J.-Y.L., A.K.G., J.S.P.) and Biochemistry (M.J.T.), Wake Forest University Health Sciences, Winston-Salem, NC; the Division of Gerontology (P.L.C.), University of Maryland School of Medicine, and the Department of Veterans Affairs and Veterans Affairs Medical Center Baltimore (J.-Y.L.), Geriatric Research, Education and Clinical Center (GRECC), Md. Current address for J.-Y.L.: Department of Nutrition and Health Sciences, University of Nebraska, Lincoln, Nebr.
* To whom correspondence should be addressed. E-mail: jparks{at}wfubmc.edu.
Objectives--The aim of this study was to determine the role of ATP binding cassette transporter A1 (ABCA1) on generation of different-sized nascent HDLs.
Methods and Results--HEK293 cells stably-transfected with ABCA1 (HEK293-ABCA1) or non-transfected (control) cells were incubated with lipid free 125I-apoA-I for 24 hours. Incubation of apoA-I with HEK293-ABCA1 cells, but not control cells, led to the formation of heterogeneous-sized, pre-
migrating nascent HDL subpopulations (pre-1 to -4) that varied in size (7.1 to 15.7 nm), lipid, and apoA-I content. Kinetic studies suggested that all subpopulations were formed simultaneously, with no evidence for a precursor-product relationship between smaller and larger-sized particles. When isolated nascent pre- HDLs (pre-1 to -4) were added back to HEK293-ABCA1 cells, their ability to bind to ABCA1 and efflux lipid was severely compromised. Heat-denaturation of pre-1 HDL resulted in partial recovery of ABCA1 binding, suggesting that initial interaction of apoA-I with ABCA1 results in a constrained conformation of apoA-I that decreases subsequent binding.
Conclusions--Interaction of apoA-I with ABCA1 results in the simultaneous generation of pre- HDLs of discrete size and chemical composition. These nascent particles are poor substrates for subsequent lipidation by ABCA1 and presumably require additional non-ABCA1-mediated lipidation for further maturation.
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