Aims: Hyperlipidaemia is a major risk factor for cardiovascular disease and atherosclerosis is the underlying cause of both myocardial infarction and stroke. We have previously shown that the Pro251 variant of perilipin-2 (PLIN2) reduces plasma triglycerides and may therefore be beneficial for atherosclerosis development. The aim of this study was to delineate the putative beneficial effects of the Pro251 variant of PLIN2 on subclinical atherosclerosis and the mechanism by which it acts.
Methods: A pan-European cohort of high-risk individuals where carotid intima media thickness has been assessed was adopted for genetic association. Human primary monocyte-derived macrophages were isolated from whole blood from carriers and non-carriers of the PLIN2 protein variant. Autophagy activity, lipid accumulation, cholesterol efflux and markers of inflammation were monitored in primary monocyte-derived macrophages. 
Results: The Pro251 variant of PLIN2 is associated with decreased intima-media thickness at baseline and 30 months follow-up. Human primary monocyte-derived macrophages from carriers of the Pro251 variant show that this variant increases autophagy activity, cholesterol efflux, and modulates the inflammatory response. Mechanistic studies show that the increase in autophagy activity is accompanied by an increase in LXR activity and that LXR and autophagy reciprocally activate each other in a feed-forward loop, regulated by CYP27A1 and 27OH-cholesterol.
Conclusion: We demonstrate that PLIN2 modulates levels of the endogenous LXR ligand 27OH-cholesterol, and thereby initiates a feed-forward loop where LXR and autophagy reciprocally activate each other; the mechanism by which perilipin-2 exerts its significant beneficial effects on subclinical atherosclerosis.

02 - SUBCLINICAL ATHEROSCLEROSIS AND ITS PROGRESSION IS MODULATED BY PLIN2 THROUGH A FEED-FORWARD LOOP BETWEEN LXR AND AUTOPHAGY