Abstract 672: Reduced "Egress" of Remnant Lipoproteins From Arterial Tissue Relative to LDL During Insulin Resistance May Explain a Preferential Role in Atherosclerosis Progression

Abstract

INTRODUCTION: There is emerging epidemiological data that supports a causative role for remnant cholesterol in atherosclerotic and CVD progression. We have shown that hepatic (apoB100) and intestinal (apoB48) lipoproteins may have disparate ‘egress’ and retention properties. Additionally we have reported that insulin resistance (IR) increases the arterial atherogenic proteoglycans. However the underlying effects of this metabolic milieu on the comparative arterial retention of both low-density lipoproteins (LDL) and chylomicron-remnant lipoproteins (CM-R) towards arterial cholesterol deposition remain elusive. Aim: To determine the comparative arterial retention and ‘egress’ of LDL and CM-R in insulin resistant carotid vessels in JCR:LA-cp rats using an ex vivo perfusion approach. METHODS: For in vivo generation of Cy5-labeled CM-R, an intravenous injection of nascent chylomicrons obtained after intragastric intralipid infusion was given to eviscerated rabbits. Labeled CM-R were collected from the plasma after density centrifugation. Human LDL was commercially obtained and was labeled with Cy3. Carotid vessels of JCR-LA:cp IR rats were perfused with Cy5-labeled remnants simultaneously with Cy3-labeled LDL. Images were quantified using confocal microscopy. RESULTS: When equivalent number of CM-R and LDL particles were perfused, a significantly greater number of LDL particles were delivered to the vessel (9-fold) as compared to CM-R. However, after extensive washout (i.e retention) significantly fewer (55% decrease) LDL particles remained in the tissue. In contrast, we observed no difference in the retention of CM-R relative to delivery experiments (no washout) perhaps due to reduced ‘egress’. Despite the greater number of LDL particles retained compared to CM-R, we observed a greater than 1.5-fold increase in total mass of cholesterol associated with CM-R as compared to cholesterol associated with LDL. CONCLUSION: There is debate whether current changes to the US clinical guidelines to move away from plasma LDL-C as an effective predictor of CVD risk. This study suggests that due to disparate ‘egress’ and retention properties of LDL and CM-R there may be a disconnection between their plasma concentration and arterial accumulation.