Acylation of lysine residues in human plasma high density lipoprotein increases stability and plasma clearance in vivo.

Although human plasma high density lipoproteins (HDL) concentrations negatively correlate with atherosclerotic cardiovascular disease, underlying mechanisms are unknown. Thus, there is continued interest in HDL structure and functionality. Numerous plasma factors disrupt HDL structure while inducing the release of lipid free apolipoprotein (apo) AI. Given that HDL is an unstable particle residing in a kinetic trap, we tested whether HDL could be stabilized by acylation with acetyl and hexanoyl anhydrides, giving AcHDL and HexHDL respectively. Lysine analysis with fluorescamine showed that AcHDL and HexHDL respectively contained 11 acetyl and 19 hexanoyl groups. Tests with biological and physicochemical perturbants showed that HexHDL was more stable than HDL to perturbant-induced lipid free apo AI formation. Like the reaction of streptococcal serum opacity factor against HDL, the interaction of HDL with its receptor, scavenger receptor class B member 1 (SR-B1), removes CE from HDL. Thus, we tested and validated the hypothesis that selective uptake of HexHDL-[ ³ H]CE by Chinese Hamster Ovary cells expressing SR-B1 is less than that of HDL-[ ³ H]CE; thus, selective SR-B1 uptake of HDL-CE depends on HDL instability. However, in mice, plasma clearance, hepatic uptake and sterol secretion into bile were faster from HexHDL-[ ³ H]CE than from HDL-[ ³ H]CE. Collectively, our data show that acylation increases HDL stability and that the reaction of plasma factors with HDL and SR-B1-mediated uptake are reduced by increased HDL stability. In vivo data suggest that HexHDL promotes charge-dependent reverse cholesterol transport, by a mechanism that increases hepatic sterol uptake via non SR-B1 receptors, thereby increasing bile acid output.
Competing Interests: The authors have no relevant conflicts of interest to disclose.
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