Abstract
Apolipoprotein E (apoE) enters the plasma as a component of discoidal HDL and is subsequently incorporated into spherical HDL, most of which contain apoE as the sole apolipoprotein. This study investigates the regulation, origins, and structure of spherical, apoE-containing HDLs and their remodeling by cholesteryl ester transfer protein (CETP). When the ability of discoidal reconstituted high density lipoprotein (rHDL) containing apoE2 [(E2)rHDL], apoE3 [(E3)rHDL], or apoE4 [(E4)rHDL] as the sole apolipoprotein to act as substrates for LCAT were compared with that of discoidal rHDL containing apoA-I [(A-I)rHDL], the rate of cholesterol esterification was (A-I)rHDL >> (E2)rHDL approximately (E3)rHDL > (E4)rHDL. LCAT also had a higher affinity for discoidal (A-I)rHDL than for the apoE-containing rHDL. When the discoidal rHDLs were incubated with LCAT and LDL, the resulting spherical (E2)rHDL, (E3)rHDL, and (E4)rHDL were larger than, and structurally distinct from, spherical (A-I)rHDL. Incubation of the apoE-containing spherical rHDL with CETP and Intralipid(R) generated large fusion products without the dissociation of apoE, whereas the spherical (A-I)rHDLs were remodeled into small particles with the formation of lipid-poor apoA-I. In conclusion, i) apoE activates LCAT less efficiently than apoA-I; ii) apoE-containing spherical rHDLs are structurally distinct from spherical (A-I)rHDL; and iii) the CETP-mediated remodeling of apoE-containing spherical rHDL differs from that of spherical (A-I)rHDL.
Highlights
Apolipoprotein E enters the plasma as a component of discoidal HDL and is subsequently incorporated into spherical HDL, most of which contain apolipoprotein E (apoE) as the sole apolipoprotein
This approach was validated for spherical (A-I)reconstituted high density lipoprotein (rHDL), for which cross-linking has been used to establish that the decrease in particle size that occurs during incubation with cholesteryl ester transfer protein (CETP) and IntralipidT is accompanied by a reduction in the number of apolipoprotein affinity for the discoidal (A-I) (apoA-I) molecules from three to two per particle [26]
75% of the apoE in normolipidemic plasma is associated with spherical HDLs that are 9.0–18.5 nm in diameter and do not contain apoA-I [2,3,4,5]
Summary
Apolipoprotein E (apoE) enters the plasma as a component of discoidal HDL and is subsequently incorporated into spherical HDL, most of which contain apoE as the sole apolipoprotein. As judged by the Km(app) values, LCAT had a greater affinity for the discoidal (A-I)rHDL than for any of the apoEcontaining rHDLs. The catalytic efficiency [Vmax/Km(app)] of the LCAT reaction was 50- to 150-fold greater for the discoidal (A-I)rHDL than for any of the apoE-containing rHDLs. Double reciprocal plots of the rate of cholesterol esterification versus substrate concentration were linear (Fig. 2, insets).
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