Abstract 538: LDL Particle Core Enrichment in Cholesteryl Oleate Results in Increased Binding to Arterial Wall Proteoglycans and Increased Atherosclerosis

Abstract

INTRODUCTION: Accumulation of lipids in the artery wall, particularly cholesteryl esters (CE), is a classic feature of atherosclerosis. Apo B-containing lipoprotein particles are the primary vehicles by which CEs are delivered across the endothelial barrier into the intima and once present in the subendothelial space these particles are subject to sequestration by native proteoglycans. Several studies in both non-human primate and murine models of atherosclerosis strongly suggest that core enrichment in cholesteryl oleate of low-density lipoprotein (LDL) particles play a significant role in determination of the extent of atherosclerosis. It has also been shown that Acyl-CoA:cholesterol O-acyltransferase 2 (ACAT2) is the enzyme responsible for cholesteryl oleate enrichment of apo B-containing lipoproteins and gene deletion of ACAT2 in animal models is protective against the development of atherosclerosis. Thus, we hypothesized that the selective accumulation of LDL within the intima is the result of LDL particle core enrichment of cholesteryl oleate that results in modification of key surface characteristics of ApoB promoting interaction with resident proteoglycans. METHODS: Apo B-100 only, LDLr -/- mice (W/T) and Apo B-100 only, LDLr-/-, ACAT2 -/- (KO) mice were fed diets enriched in either cis-monounsaturated fatty acids (cis-MUFA) or n-3 polyunsaturated fatty acids (n-3 PUFA) for 16 weeks. Blood and plasma was harvested and LDL particles were isolated by size exclusion chromatography. The major lipid constituents of the LDL particle were measured along with the fatty acids of the cholesteryl ester fraction of the particle core. LDL affinity to arterial proteoglycans was determined using an immunocapture surface plasmon resonance (SPR) technique we developed. Atherosclerosis was quantified by measuring the cholesterol content of the aorta. RESULTS: W/T mice fed a cis-MUFA diet displayed the highest degree of cholesteryl oleate packaging into the particle core and the highest propensity to bind to arterial proteoglycans. Feeding a diet enriched in n-3 PUFA and/or knocking out ACAT2 successfully inhibited the packaging of cholesteryl oleate into the LDL particles. Accompanying this decrease in cholesteryl oleate content was a significant decrease in binding to arterial proteoglycans and development of atherosclerosis. CONCLUSION: Elimination of cholesteryl oleate from the LDL particle core results in significantly less binding to arterial wall proteoglycans and in turn, less development of atherosclerosis.