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Journal of Lipid Research, Vol. 51, 324-333, February 2010
Copyright © 2010 by American Society for Biochemistry and Molecular Biology

Effects of cholesterol on thermal stability of discoidal high density lipoproteins^[S]

Shobini Jayaraman¹, Sangeeta Benjwal, Donald L. Gantz and Olga Gursky

Department of Physiology and Biophysics, Boston University School of Medicine, Boston, MA 02118

¹ To whom correspondence should be addressed. e-mail: shobini{at}bu.edu

Reverse cholesterol transport in plasma involves variations in HDL cholesterol concentration. To understand physicochemical and functional implications of such variations, we analyzed stability of reconstituted HDL containing human apolipoproteins (apoA-I, apoA-II, or apoC-I), phosphatidylcholines varying in chain length (12–18 carbons) and unsaturation (0 or 1), and 0–35 mol% cholesterol. Lipoprotein heat denaturation was monitored by circular dichroism for protein unfolding/dissociation and by light scattering for particle fusion. We found that cholesterol stabilizes relatively unstable complexes; for example, incorporation of 10–30 mol% cholesterol in apoC-I:dimyristoyl phosphatidylcholine complexes increased their kinetic stability by G* 1 kcal/mol. In more stable complexes containing larger proteins and/or longer-chain lipids, incorporation of 10% cholesterol did not significantly alter the disk stability; however, 15% or more cholesterol destabilized the apoA-I-containing complexes and led to vesicle formation. Thus, cholesterol tends to stabilize less stable lipoproteins, apparently by enhancing favorable packing interactions, but in more stable lipoproteins, where such interactions are already highly optimized, the stabilizing effect of cholesterol decreases and, eventually, becomes destabilizing. These results help uncouple the functional roles of particle stability and chain fluidity and suggest that structural disorder in HDL surface, rather than chain fluidity, is an important physicochemical determinant of HDL function.—Jayaraman, S., S. Benjwal, D. L. Gantz, and O. Gursky. Effects of cholesterol on thermal stability of discoidal high density lipoproteins. J. Lipid Res. 2010. 51: 324–333.

Supplementary key words kinetic stability • protein unfolding rate • lipoprotein fusion • acyl chain fluidity • reverse cholesterol transport

Abbreviations: apo, apolipoprotein; CD, circular dichroism; Ch, unesterified cholesterol; DLPC, dilinoleyl phosphatidylcholine; DMPC, dimyristoyl phosphatidylcholine; DPPC, dipalmitoyl phosphatidylcholine; DSC, differential scanning calorimetry; EM, electron microscopy; PC, phosphatidylcholine; POPC, palmitoyl oleoyl phosphatidylcholine; RCT, reverse cholesterol transport; rHDL, reconstituted high-density lipoprotein; T-jump, temperature jump

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