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

Autor: Anders Hamsten, Elena Tremoli, Ewa Ehrenborg, V. Janas, A. Franco-Cereceda, Matteo Pirro, Damiano Baldassarre, Marju Orho-Melander, Karl Gertow, S. Pourteymour, Peter Eriksson, Paolo Parini, Fabrizio Veglia, Peter Saliba-Gustafsson, Matteo Pedrelli, Andries J. Smit, Sudhir Kurl, Joëlle Magné, Rainer Rauramaa, Isabel Gonçalves, Jan Borén, U de Faire, S.E. Humphries, P. Giral, O. Werngren
Přispěvatelé: Groningen Kidney Center (GKC), Vascular Ageing Programme (VAP), Lifestyle Medicine (LM), Translational Immunology Groningen (TRIGR)
Jazyk: angličtina
Rok vydání: 2019
Předmět:
0301 basic medicine
Male
STIMULATION
EFFLUX
Stimulation
030204 cardiovascular system & hematology
Carotid Intima-Media Thickness
27OH-cholesterol
atherosclerosis
autophagy
liver-X-receptor
PLIN2
PROTECTS
chemistry.chemical_compound
0302 clinical medicine
MACROPHAGE FOAM CELLS
CYP27A1
Longitudinal Studies
Receptor
Whole blood
Liver X Receptors
REVERSE CHOLESTEROL TRANSPORT
Reverse cholesterol transport
Middle Aged
3. Good health
Europe
RECEPTORS
Disease Progression
Original Article
liver‐X‐receptor
Female
27OH‐cholesterol
Corrigendum
SER251PRO
medicine.medical_specialty
Lipoproteins
METABOLISM
Perilipin-2
03 medical and health sciences
Internal medicine
Internal Medicine
medicine
Humans
Liver X receptor
Aged
ACCUMULATION
IDENTIFICATION
Cholesterol
business.industry
Macrophages
Autophagy
Original Articles
030104 developmental biology
Endocrinology
chemistry
business
Foam Cells
Zdroj: Journal of Internal Medicine. Wiley
J Intern Med
Journal of Internal Medicine
ISSN: 0954-6820
Popis: 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.
Databáze: OpenAIRE
Externí odkaz: