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

S Kurl, E Ehrenborg, P Parini, J Magné, P Eriksson, J Borén, A Franco-Cereceda, M Orho-Melander, I Gonçalves, A Hamsten, S E Humphries, U de Faire, M Pirro, P Saliba-Gustafsson, P Giral, A J Smit, R Rauramaa, F Veglia, E Tremoli, D Baldassarre, S Pourteymour, V Janas, O Werngren, K Gertow, M Pedrelli

Journal: Journal of internal medicine 2020;286(6):660-675

PMID: 31251843

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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.

Address: Cardiovascular Medicine Unit, Department of Medicine, Center for Molecular Medicine at BioClinicum, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.; Cardiovascular Medicine, Stanford University School of Medicine, Palo Alto, California, USA.; Division of Clinical Chemistry, Department of Laboratory Medicine, Karolinska Institutet Huddinge, Huddinge, Sweden.; Department of Medical Biotechnology and Translational Medicine, Università degli Studi di Milano, Milan, Italy.; Centro Cardiologico Monzino, IRCCS, Milan, Italy.; Dipartimento di Scienze Farmacologiche e Biomolecolari, Università di Milano, Milan, Italy.; Foundation for Research in Health Exercise and Nutrition, Kuopio Research Institute of Exercise Medicine, Kuopio, Finland.; Department of Medicine, University Medical Center Groningen, Groningen, The Netherlands.; Assistance Publique Hopitaux de Paris, Service Endocrinologie-Metabolisme, Groupe Hospitalier Pitie-Salpetriere, Unites de Prevention Cardiovasculaire, Paris, France.; Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland.; Unit of Internal Medicine, Angiology and Arteriosclerosis Diseases, Department of Medicine, University of Perugia, Perugia, Italy.; Division of Cardiovascular Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.; Centre for Cardiovascular Genetics, Institute Cardiovascular Science, University College London, London, UK.; Experimental Cardiovascular Research Group and Cardiology Department, Clinical Research Center, Clinical Sciences Malmö, Lund University, Lund, Sweden.; Department of Clinical Sciences in Malmö, Lund University Diabetes Centre, Lund University, Lund, Sweden.; Cardiothoracic Surgery Unit, Department of Molecular Medicine and Surgery, Karolinska Institutet at Karolinska University Hospital Solna, Solna, Sweden.; Department of Molecular and Clinical Medicine/Wallenberg Laboratory, University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden.; St Jude Children's Research Hospital, Department of Immunology, Memphis, Tennessee, USA.; Metabolism Unit, Department of Medicine, Karolinska Institutet at Karolinska University Hospital Huddinge, Huddinge, Sweden.

DOI: 10.1111/joim.12951

Link outs

Free resources

Full Text Sources:

Medical:

https://medlineplus.gov/atherosclerosis.html

Research Materials:

https://antibodies.cancer.gov/detail/CPTC-PLIN2-1

MeSH Terms: Aged, Atherosclerosis, Autophagy, Carotid Intima-Media Thickness, Disease Progression, Europe, Female, Foam Cells, Humans, Lipoproteins, Liver X Receptors, Longitudinal Studies, Macrophages, Male, Middle Aged, Perilipin-2