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

Research output: Contribution to journalArticle

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.

Details

Authors
  • 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. Gonçalves
  • M. Orho-Melander
  • A. Franco-Cereceda
  • J. Borén
  • P. Eriksson
  • J. Magné
  • P. Parini
  • E. Ehrenborg
  • IMPROVE Study Group
Organisations
External organisations
  • Karolinska University Hospital
  • Stanford University
  • Karolinska Institutet
  • University of Milan
  • Centro Cardiologico Monzino
  • University of Eastern Finland
  • University Medical Center Groningen
  • Pitié Salpetriere University Paris
  • University of Perugia
  • University College London
  • St Jude Children´s Research Hospital, Memphis
  • University of Gothenburg
  • Sahlgrenska University Hospital
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Cardiac and Cardiovascular Systems

Keywords

  • 27OH-cholesterol, atherosclerosis, autophagy, liver-X-receptor, PLIN2
Original languageEnglish
Pages (from-to)660-675
Number of pages16
JournalJournal of Internal Medicine
Volume286
Issue number6
Publication statusPublished - 2019
Publication categoryResearch
Peer-reviewedYes