Abstract 551: Is Free Cholesterol Bioavailability a Determinant of Dysfunctional, Atherogenic High Density Lipoproteins? Refining the Model of Reverse Cholesterol Transport

Abstract

Although cardiovascular disease (CVD) negatively correlates with high-density lipoprotein-cholesterol (HDL-C) levels, to date HDL-raising therapies have not reduced CVD; thus, in the context of reverse cholesterol transport (RCT), HDL quality, i.e., functionality, may be more important to atheroprotection than HDL quantity. The current RCT model comprises free cholesterol (FC) efflux from macrophages to apo AI to give nHDL, LCAT-mediated nHDL-FC esterification forming mature HDL, SR-B1-mediated hepatic uptake of HDL lipids, followed by sterol metabolism and excretion. Our recent studies challenge this model: We observed that nHDL apo AI, FC and phospholipid (PL) metabolically segregate. In mice, plasma nHDL FC and PL are hepatically cleared with t 1/2 ~3 min; nHDL-apo AI is cleared more slowly with t 1/2 = 460 min. FC esterification is 100X slower, and thus a minor RCT step. These results and the observation that nHDL is FC-rich (~64 mol%) led to a revised model of RCT, with a focus on FC bioavailabilty rather than CE uptake. HDL from SR-B1 -/- mice is also FC-rich and associated with atherosclerosis. Moreover, the magnitude of HDL-C content/particle is associated with carotid artery atheroprogression (Qi et al JACC 2015 65:355-363), and HDL from hyperlipidemic HIV patients, which are at increased CVD risk, also have a high mol% FC compared to controls (29 vs 16 mol%, p<0.05). Thus, we hypothesize that high HDL-FC bioavailability, measured as the product of mol% HDL-FC and HDL particle number, is a metric for dysfunctional, atherogenic HDL. We studied SRB1 -/- mice, which are atherosusceptible and a model of dysfunctional HDL. Compared to WT mice, SR-B1 -/- mice have a higher HDL particle number and mol% FC (~58 vs. 15). Compared to WT HDL, SRB1 -/- HDL is more resistant to disruption by GdmHCl and serum opacity factor, indicating a resistance to remodeling. We plan to compare FC bioavailability of WT and SRB1 -/- HDL according to the kinetics of HDL-FC transfer to LDL. Our studies will determine if increased HDL-FC bioavailability in dysfunctional FC-rich HDL supports whole-body hypercholesterolemia that could increase CVD risk.