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Abstract
Lipoprotein(a) [Lp(a)] is assembled by the binding of apolipoprotein B (apoB) lysine residues on LDL to lysine binding sites in apolipoprotein(a) [apo(a)] and the subsequent formation of a disulphide bond between apoB and apo(a). In this study, we induced changes in apoB conformation by adding phospholipids to LDL and tested the effect of the altered apoB conformation on Lp(a) assembly. The addition of dimyristoylphosphatidylcholine (DMPC) to isolated LDL induced a decrease in the alpha-helical content of apoB and increased the immunoreactivity of the apoB C terminus toward monoclonal antibodies in the region. These conformational changes were associated with a reduction in the ability of the DMPC-modified LDL to form Lp(a) in in vitro assays. Furthermore, administration of DMPC to Lp(a) transgenic mice lead to a significant but transient decrease in Lp(a) levels (18.6% decrease at 2 h, P < 0.001) which coincided with the association of DMPC with LDL in plasma. Our study shows that changes in apoB conformation in the C-terminal region alter the exposure of sequences required for Lp(a) assembly and reduce the formation of Lp(a) both in vitro and in vivo. We conclude that manipulation of LDL surface phospholipids alters Lp(a) levels.
Highlights
Lipoprotein(a) [Lp(a)] is assembled by the binding of apolipoprotein B lysine residues on LDL to lysine binding sites in apolipoprotein(a) [apo(a)] and the subsequent formation of a disulphide bond between apoB and apo(a)
We investigated the effect of dimyristoylphosphatidylcholine (DMPC) on the conformation of apoB on LDL and the efficiency of Lp(a) assembly both in vitro and in vivo
ApoB is of particular interest because it is known to change conformation with changing lipid composition of the associated lipoprotein [17, 20, 31]
Summary
Lipoprotein(a) [Lp(a)] is assembled by the binding of apolipoprotein B (apoB) lysine residues on LDL to lysine binding sites in apolipoprotein(a) [apo(a)] and the subsequent formation of a disulphide bond between apoB and apo(a). We induced changes in apoB conformation by adding phospholipids to LDL and tested the effect of the altered apoB conformation on Lp(a) assembly. The addition of dimyristoylphosphatidylcholine (DMPC) to isolated LDL induced a decrease in the a-helical content of apoB and increased the immunoreactivity of the apoB C terminus toward monoclonal antibodies in the region. These conformational changes were associated with a reduction in the ability of the DMPC-modified LDL to form Lp(a) in in vitro assays. Our study shows that changes in apoB conformation in the C-terminal region alter the exposure of sequences required for Lp(a) assembly and reduce the formation of Lp(a) both in vitro and in vivo.
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