Submitted on February 28, 2008
Revised on April 30, 2008
Accepted on April 30, 2008
Effects of acyl chain length, unsaturation and pH on thermal stability of model discoidal high-density lipoproteins
Madhumita Guha, Donald L. Gantz, and Olga Gursky
Physiology and Biophysics, Boston University School of Medicine, Boston, MA 02118
Corresponding Author: gursky{at}bu.edu
High-density lipoproteins 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 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 DeltaG*(37oC)=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.
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