Ether Phosphatidylcholines: Comparison of Miscibility with Ester Phosphatidylcholines and Sphingomyelin, Vesicle Fusion, and Association with Apolipoprotein A-I

Nonhydrolyzable matrices of ether-linked phosphatidylcholines (PCs) and sphingomyelin have been used to study the mechanism of action of lipolytic enzymes. Since ether PCs, sphingomyelin, and ester PCs vary in the number of hydrogen bond donors and acceptors in the carbonyl region of the bilayer, we have examined several physical properties of ether PCs and sphingomyelin in model systems to validate their suitability as nonhydrolyzable lipid matrices. The intermolecular interactions of ether PCs with ester PCs, sphingomyelin, and cholesterol were investigated by differential scanning calorimetry. Phase diagrams constructed from the temperature dependence of the gel to liquid-crystalline phase transition of 1,2-O-dihexadecyl-sn-glycero-3-phosphocholine (DPPC-ether) and 1,2-O-ditetradecyl-sn-glycero-3-phosphocholine (DMPC-ether) with both 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) and 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) demonstrated complete lipid miscibility in the gel and liquid-crystalline phases. Additionally, phase diagrams of egg yolk sphingomyelin (EYSM) with DMPC or DMPC-ether and 1,2-distearoyl-sn-glycero-S-phosphocholine (DSPC) or 1,2-O-dioctadecyl-sn-glycero-S-phosphocholine (DSPC-ether) demonstrated no major differences in miscibility of EYSM in ester and ether PCs. The effect of 10 mol % cholesterol on the thermal transitions of mixtures of ester and ether PCs also indicates little preference of cholesterol for either lipid. The fusion of small single bilayer vesicles of DMPC, DMPC-ether, DPPC, and DPPC-ether to larger aggregates as determined by gel filtration indicated that the ester PC vesicles were somewhat more stable. The rate of association of apolipoprotein A-I with DMPC or DMPC-ether multilamellar liposomes was compared. The rate was fastest at the gel → liquid-crystalline transition temperature (T_c) of either lipid and was consistent with the insertion of the protein into lattice defects in the lipid matrix. Ether PCs interact with ester PCs, sphingomyelin, cholesterol, and apolipoproteins in a manner similar to ester PCs. The interaction between these lipids appears to be dominated by hydrocarbon chain interactions instead of the hydrogen bonding groups in the carbonyl region. Thus, ether PCs appear to be suitable analogues of the ester PCs for the elucidation of structural-functional mechanisms of lipolysis.