Effects of the neutral lipid content of high density lipoprotein on apolipoprotein A-I structure and particle stability.
Alterations in high density lipoprotein (HDL) composition that occur in dyslipidemic states may modulate a number of events involved in cholesterol homeostasis. To elucidate the details of how HDL-core composition can affect the molecular structure of different kinds of HDL particles, the conformation and stability of apoA-I have been investigated in homogeneous recombinant HDL particles (LpA-I) containing palmitoyloleoyl phosphatidylcholine (POPC), triolein (TG), and/or cholesteryl linoleate (CE). In a discoidal particle containing two molecules of apoA-I and 85 molecules of POPC, apoA-I exhibits an alpha-helix content of 70% and a free energy of stability of its alpha-helical segments (delta G0D) of 2.2 kcal/mol. Inclusion of eight molecules of TG into the complex significantly reduces the alpha-helix content and stability of apoA-I, whereas inclusion of four molecules of CE into the complex has an opposite effect in that the alpha-helix content is significantly reduced and the stability of the remaining alpha-helical structure of apoA-I is increased. Neutral lipids have a different effect on apoA-I conformation in spherical LpA-I particles. In a sonicated-spherical LpA-I particle containing two molecules of apoA-I and 70 molecules of POPC, apoA-I exhibits an alpha-helix content of about 60% and a delta G0D of 1.2 kcal/mol apoA-I. Inclusion of either 10 molecules of TG or six molecules of CE into such a particle increases both the alpha-helix content and stability of apoA-I. Increasing the CE/TG ratio in LpA-I particles that contain both neutral lipids enhances the stability of the alpha-helical segments. ApoA-I molecules tend to dissociate and cause particle instability when delta G0D for the lipid-bound alpha-helices is less than that for helices in the lipid-free state. The stabilities of both discoidal and spherical LpA-I particles are relatively low when the only neutral lipid present is TG but the particle stability is enhanced by the presence of CE molecules. Such dissociation of apoA-I molecules from LpA-I particles that have a low CE/TG ratio would be promoted in the hypertriglyceridemic state in vivo.
Sparks
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DL
Lipoproteins and Atherosclerosis Group, University of Ottawa Heart Institute, Ontario, Canada.
Davidson
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Lund-Katz
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Phillips
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MC
D016632:Apolipoprotein A-I / Q000737:chemistry*; D002788:Cholesterol Esters / Q000737:chemistry; D004355:Drug Stability; D004563:Electrochemistry; D006801:Humans; D066298:In Vitro Techniques; D008055:Lipids / Q000737:chemistry*; D008075:Lipoproteins, HDL / Q000737:chemistry*; D008854:Microscopy, Electron; D008968:Molecular Conformation; D015394:Molecular Structure; D010713:Phosphatidylcholines / Q000737:chemistry; D014304:Triolein / Q000737:chemistry
D016632:Apolipoprotein A-I; D002788:Cholesterol Esters; D008055:Lipids; D008075:Lipoproteins, HDL; D010713:Phosphatidylcholines; D014304:Triolein; C021976:cholesteryl linoleate; C028694:1-palmitoyl-2-oleoylphosphatidylcholine