• P Saliba-Gustafsson, M Pedrelli, K Gertow, O Werngren, V Janas, S Pourteymour, D Baldassarre, E Tremoli, F Veglia, R Rauramaa, A J Smit, P Giral, S Kurl, M Pirro, U de Faire, S E Humphries, A Hamsten, IMPROVE Study Group, I Gonçalves, M Orho-Melander, A Franco-Cereceda, J Borén, P Eriksson, J Magné, P Parini, and E Ehrenborg.
• Cardiovascular Medicine Unit, Department of Medicine, Center for Molecular Medicine at BioClinicum, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.
• J. Intern. Med. 2019 Dec 1; 286 (6): 660-675.

BackgroundHyperlipidaemia 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 reduces plasma triglycerides and may therefore be beneficial to reduce atherosclerosis development.ObjectiveWe sought to delineate putative beneficial effects of the Pro251 variant of perlipin-2 on subclinical atherosclerosis and the mechanism by which it acts.MethodsA pan-European cohort of high-risk individuals where carotid intima-media thickness has been assessed was adopted. Human primary monocyte-derived macrophages were prepared from whole blood from individuals recruited by perilipin-2 genotype or from buffy coats from the Karolinska University hospital blood central.ResultsThe Pro251 variant of perilipin-2 is associated with decreased intima-media thickness at baseline and over 30 months of follow-up. Using human primary monocyte-derived macrophages from carriers of the beneficial Pro251 variant, we show that this variant increases autophagy activity, cholesterol efflux and a controlled inflammatory response. Through extensive mechanistic studies, we demonstrate that increase in autophagy activity is accompanied with an increase in liver-X-receptor (LXR) activity and that LXR and autophagy reciprocally activate each other in a feed-forward loop, regulated by CYP27A1 and 27OH-cholesterol.ConclusionsFor the first time, we show that perilipin-2 affects susceptibility to human atherosclerosis through activation of autophagy and stimulation of cholesterol efflux. We demonstrate that perilipin-2 modulates levels of the LXR ligand 27OH-cholesterol and initiates a feed-forward loop where LXR and autophagy reciprocally activate each other; the mechanism by which perilipin-2 exerts its beneficial effects on subclinical atherosclerosis.© 2019 The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine.

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