Journal
BIOCHEMISTRY
Volume 47, Issue 16, Pages 4770-4779Publisher
AMER CHEMICAL SOC
DOI: 10.1021/bi7023354
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Funding
- NHLBI NIH HHS [HL 77268, P01 HL030086, R01 HL086798, HL 086708, R01 HL077268-02, R01 HL077268, R01 HL077268-03, R01 HL077268-06, HL 086798] Funding Source: Medline
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High-density lipoprotein (HDL) mediates reverse cholesterol transport (RCT), wherein excess cholesterol is conveyed from peripheral tissues to the liver and steroidogenic organs. During this process HDL continually transitions between subclass sizes, each with unique biological activities. For instance, RCT is initiated by the interaction of lipid-free/lipid-poor apolipoprotein A-I (apoA-I) with ABCA1, a membrane-associated lipid transporter, to form nascent HDL. Because nearly all circulating apoA-I is lipid-bound, the source of lipid-free/lipid-poor apoA-1 is unclear. Lecithin: cholesterol acyltransferase (LCAT) then drives the conversion of nascent HDL to spherical HDL by catalyzing cholesterol esterification, an essential step in RCT. To investigate the relationship between HDL particle. size and events critical to RCT such as LCAT activation and lipid-free apoA-1 production for ABCA1 interaction, we reconstituted five subclasses of HDL particles (rHDL of 7.8, 8.4, 9.6, 12.2, and 17.0 nm in diameter, respectively) using various molar ratios of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine, free cholesterol, and apoA1. Kinetic analyses of this comprehensive array of rHDL particles suggest that apoA-I stoichiometry in rHDL is a critical factor governing LCAT activation. Electron microscopy revealed specific morphological differences in the HDL subclasses that may affect functionality. Furthermore, stability measurements demonstrated that the previously uncharacterized 8.4 nm rHDL particles rapidly convert to 7.8 nm particles, concomitant with the dissociation of lipid-free/lipid-poor apoA-1. Thus, lipid-free/lipid-poor apoA-1 generated by the remodeling of HDL may be an essential intermediate in RCT and HDL's in vivo maturation.
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