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We have previously shown that the Pro251 variant of perilipin\u20102 reduces plasma triglycerides and may therefore be beneficial to reduce atherosclerosis development.<\/jats:p><\/jats:sec><jats:sec><jats:title>Objective<\/jats:title><jats:p>We sought to delineate putative beneficial effects of the Pro251 variant of perlipin\u20102 on subclinical atherosclerosis and the mechanism by which it acts.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>A pan\u2010European cohort of high\u2010risk individuals where carotid intima\u2010media thickness has been assessed was adopted. Human primary monocyte\u2010derived macrophages were prepared from whole blood from individuals recruited by perilipin\u20102 genotype or from buffy coats from the Karolinska University hospital blood central.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The Pro251 variant of perilipin\u20102 is associated with decreased intima\u2010media thickness at baseline and over\u00a030\u00a0months of\u00a0follow\u2010up. Using human primary monocyte\u2010derived 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\u2010X\u2010receptor (LXR) activity and that LXR and autophagy reciprocally activate each other in a feed\u2010forward loop, regulated by <jats:italic>CYP27A1<\/jats:italic> and 27OH\u2010cholesterol.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>For the first time, we show that perilipin\u20102 affects susceptibility to human atherosclerosis through activation of autophagy and stimulation of cholesterol efflux. We demonstrate that perilipin\u20102 modulates levels of the LXR ligand 27OH\u2010cholesterol and initiates a feed\u2010forward loop where LXR and autophagy reciprocally activate each other; the mechanism by which perilipin\u20102 exerts its beneficial effects on subclinical atherosclerosis.<\/jats:p><\/jats:sec>","DOI":"10.1111\/joim.12951","type":"journal-article","created":{"date-parts":[[2019,6,28]],"date-time":"2019-06-28T16:24:36Z","timestamp":1561739076000},"page":"660-675","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Subclinical atherosclerosis and its progression are modulated by <i>PLIN2<\/i> through a feed\u2010forward loop between LXR and autophagy"],"prefix":"10.1111","volume":"286","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7807-9009","authenticated-orcid":false,"given":"P.","family":"Saliba\u2010Gustafsson","sequence":"first","affiliation":[{"name":"Cardiovascular Medicine Unit, 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