Regulation of reconstituted high density lipoprotein structure and remodeling by apolipoprotein E

Kerry Anne Rye, Richard Bright, Maria Psaltis, and Philip J. Barter

Lipid Research Group, The Heart Research Institute, Camperdown, New South Wales 2050

Corresponding Author: karye{at}ozemail.com.au

Apolipoprotein (apo) E is synthesized in the liver, 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. Despite being the main source of apoE for triglyceride-rich lipoproteins, little is known about the regulation, origins and structure of spherical apoE-containing HDL, or their remodeling by plasma factors such as cholesteryl ester transfer protein (CETP). These issues are addressed in the present study. The ability of discoidal reconstituted HDL (rHDL) containing either apoE2, (E2)rHDL, apoE3, (E3)rHDL, or apoE4, (E4)rHDL as the sole apolipoprotein to act as substrates for LCAT was compared to that of discoidal (A-I)rHDL. The rate of cholesterol esterification in the (A-I)rHDL >> (E2)rHDL ~ (E3)rHDL > (E4)rHDL. LCAT also had a higher affinity for the discoidal (A-I)rHDL than for the apoE-containing rHDL. The discoidal rHDL were converted into spherical particles by incubation with LCAT and LDL. The resulting spherical (E2)rHDL, (E3)rHDL and (E4)rHDL were larger than, and structurally distinct from, the spherical (A-I)rHDL. Incubation of the apoE-containing spherical rHDL with CETP and Intralipid® generated large fusion products without the dissociation of apoE, whereas the spherical (A-I)rHDL were remodelled into small particles in a process that generated lipid-poor apoA-I. It is concluded that (i) apoE activates LCAT less efficiently than apoA-I, (ii) LCAT converts apoE-containing discoidal rHDL into spherical particles that are structurally distinct from spherical (A-I)rHDL, and (iii) the CETP-mediated remodelling of apoE-containing spherical rHDL is distinct from that of spherical (A-I)rHDL.

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