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Photo: KG Pressfoto

Marju Orho-Melander

Professor

Photo: KG Pressfoto

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

Author

  • 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

Summary, in English

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.

Department/s

  • EXODIAB: Excellence of Diabetes Research in Sweden
  • Cardiovascular Research - Translational Studies
  • Diabetes - Cardiovascular Disease
  • EpiHealth: Epidemiology for Health

Publishing year

2019

Language

English

Pages

660-675

Publication/Series

Journal of Internal Medicine

Volume

286

Issue

6

Document type

Journal article

Publisher

Wiley-Blackwell

Topic

  • Cardiac and Cardiovascular Systems

Keywords

  • 27OH-cholesterol
  • atherosclerosis
  • autophagy
  • liver-X-receptor
  • PLIN2

Status

Published

Research group

  • Cardiovascular Research - Translational Studies
  • Diabetes - Cardiovascular Disease

ISBN/ISSN/Other

  • ISSN: 0954-6820