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Papers In Press, published online ahead of print August 1, 2008
J. Lipid Res., doi:10.1194/jlr.M800106-JLR200

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Journal of Lipid Research, Vol. 49, 1752-1761, August 2008
Copyright © 2008 by American Society for Biochemistry and Molecular Biology

Effects of acyl chain length, unsaturation, and pH on thermal stability of model discoidal HDLs^*,

Madhumita Guha, Donald L. Gantz and Olga Gursky¹

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

^* This work was supported by the National Institutes of Health grants GM067260 and HL026355.

The online version of this article (available at http://www.jlr.org) contains supplemental data in the form of four figures.

Published, JLR Papers in Press, May 1, 2008.

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

HDLs prevent atherosclerosis by removing excess cell cholesterol. Lipid composition affects HDL functions in cholesterol removal, yet its effects on the disk stability remain unclear. We hypothesize that reduced length or increased cis-unsaturation of phosphatidylcholine acyl chains destabilize discoidal HDL and promote protein dissociation and lipoprotein fusion. To test this hypothesis, we determined thermal stability of binary complexes reconstituted from apoC-I and diacyl PCs containing 12–18 carbons with 0–2 cis-double bonds. Kinetic analysis using circular dichroism shows that, for fully saturated PCs, chain length increase by two carbons stabilizes lipoprotein by G* (37°C) 1.4 kcal/mol, suggesting that hydrophobic interactions dominate the disk stability; distinct effects of pH and salt indicate contribution of electrostatic interactions. Similarly, apoA-I-containing disks show increased stability with increasing chain length. Acyl chain unsaturation reduces disk stability. In summary, stability of discoidal HDL correlates directly with fatty acyl chain length and saturation: the longer and more fully saturated are the chains, the more extensive are the stabilizing lipid-protein and lipid-lipid interactions and the higher is the free energy barrier for protein dissociation and lipoprotein fusion. This sheds new light on the existing data of cholesterol efflux to discoidal HDL and suggests that moderate lipoprotein destabilization facilitates cholesterol insertion.

Supplementary key words phosphatidylcholine • apoC-I • apoA-I • kinetic stability • HDL fusion • hydrophobic and electrostatic interactions • cooperative unit • reverse cholesterol transport

Abbreviations: apo, apolipoprotein; CD, circular dichroism; DLPC, dilauroyl PC; DMPC, dimyristoyl PC; DPPC, dipalmitoyl PC; DSC, differential scanning calorimetry; DSPC, distearoyl PC; EM, electron microscopy; PC, phosphatidylcholine; PLPC, palmitoyl-linoleoyl PC; POPC, palmitoyl-oleoyl PC; RCT, reverse cholesterol transport; rHDL, reconstituted HDL; T-jump, temperature jump

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