Journal
JOURNAL OF INTERNAL MEDICINE
Volume 286, Issue 6, Pages 660-675Publisher
WILEY
DOI: 10.1111/joim.12951
Keywords
27OH-cholesterol; atherosclerosis; autophagy; liver-X-receptor; PLIN2
Categories
Funding
- Swedish Research Council [8691, 09533]
- Swedish Heart-Lung Foundation
- Marianne and Marcus Wallenberg's Foundation
- Swedish Medical Society
- Swedish Foundation for Strategic Research
- Skane University Hospital Funds
- Karolinska Institutet
- European Commission [QLG1-CT-2002-00896]
- Knut and Alice Wallenberg Foundation
- Foundation for Strategic Research
- Stockholm County Council [592229]
- Strategic Cardiovascular and Diabetes Program of Karolinska Institutet
- Strategic Cardiovascular and Diabetes Program of Stockholm County Council
- European Union Framework Program 7 (FP7/2007-2013) for Innovative Medicine Initiative [IMI/115006]
- Academy of Finland [110413]
- British Heart Foundation [RG2008/08, RG2008/014]
- Italian Ministry of Health
- Academy of Finland (AKA) [110413, 110413] Funding Source: Academy of Finland (AKA)
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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.
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