Subclinical atherosclerosis and its progression are modulated by PLIN2 through a feed-forward loop between LXR and autophagy

IMPROVE Study Grp, 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, I. Goncalves, M. Orho-MelanderA. Franco-Cereceda, J. Boren, P. Eriksson, J. Magne, P. Parini, E. Ehrenborg*

*Corresponding author for this work

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Abstract

Background 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 reduces plasma triglycerides and may therefore be beneficial to reduce atherosclerosis development. Objective We sought to delineate putative beneficial effects of the Pro251 variant of perlipin-2 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. 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. Results The 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. Conclusions For 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.

Original languageEnglish
Number of pages16
JournalJournal of Internal Medicine
DOIs
Publication statusPublished - 29-Jul-2019

Keywords

  • 27OH-cholesterol
  • atherosclerosis
  • autophagy
  • liver-X-receptor
  • PLIN2
  • REVERSE CHOLESTEROL TRANSPORT
  • MACROPHAGE FOAM CELLS
  • ACCUMULATION
  • EFFLUX
  • IDENTIFICATION
  • STIMULATION
  • METABOLISM
  • RECEPTORS
  • SER251PRO
  • PROTECTS

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