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

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...

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Autores principales: Saliba‐Gustafsson, P., Pedrelli, M., Gertow, K., Werngren, O., Janas, V., Pourteymour, S., Baldassarre, D., Tremoli, E., Veglia, F., Rauramaa, R., Smit, A.J., Giral, P., Kurl, S., Pirro, M., de Faire, U., Humphries, S.E., Hamsten, A., Gonçalves, I., Orho‐Melander, M., Franco‐Cereceda, A., Borén, J., Eriksson, P., Magné, J., Parini, P., Ehrenborg, E.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6899829/
https://www.ncbi.nlm.nih.gov/pubmed/31251843
http://dx.doi.org/10.1111/joim.12951
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author Saliba‐Gustafsson, P.
Pedrelli, M.
Gertow, K.
Werngren, O.
Janas, V.
Pourteymour, S.
Baldassarre, D.
Tremoli, E.
Veglia, F.
Rauramaa, R.
Smit, A.J.
Giral, P.
Kurl, S.
Pirro, M.
de Faire, U.
Humphries, S.E.
Hamsten, A.
Gonçalves, I.
Orho‐Melander, M.
Franco‐Cereceda, A.
Borén, J.
Eriksson, P.
Magné, J.
Parini, P.
Ehrenborg, E.
author_facet Saliba‐Gustafsson, P.
Pedrelli, M.
Gertow, K.
Werngren, O.
Janas, V.
Pourteymour, S.
Baldassarre, D.
Tremoli, E.
Veglia, F.
Rauramaa, R.
Smit, A.J.
Giral, P.
Kurl, S.
Pirro, M.
de Faire, U.
Humphries, S.E.
Hamsten, A.
Gonçalves, I.
Orho‐Melander, M.
Franco‐Cereceda, A.
Borén, J.
Eriksson, P.
Magné, J.
Parini, P.
Ehrenborg, E.
author_sort Saliba‐Gustafsson, P.
collection PubMed
description 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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spelling pubmed-68998292019-12-19 Subclinical atherosclerosis and its progression are modulated by PLIN2 through a feed‐forward loop between LXR and autophagy Saliba‐Gustafsson, P. Pedrelli, M. Gertow, K. Werngren, O. Janas, V. Pourteymour, S. Baldassarre, D. Tremoli, E. Veglia, F. Rauramaa, R. Smit, A.J. Giral, P. Kurl, S. Pirro, M. de Faire, U. Humphries, S.E. Hamsten, A. Gonçalves, I. Orho‐Melander, M. Franco‐Cereceda, A. Borén, J. Eriksson, P. Magné, J. Parini, P. Ehrenborg, E. J Intern Med Original Articles 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. John Wiley and Sons Inc. 2019-07-29 2019-12 /pmc/articles/PMC6899829/ /pubmed/31251843 http://dx.doi.org/10.1111/joim.12951 Text en © 2019 The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Articles
Saliba‐Gustafsson, P.
Pedrelli, M.
Gertow, K.
Werngren, O.
Janas, V.
Pourteymour, S.
Baldassarre, D.
Tremoli, E.
Veglia, F.
Rauramaa, R.
Smit, A.J.
Giral, P.
Kurl, S.
Pirro, M.
de Faire, U.
Humphries, S.E.
Hamsten, A.
Gonçalves, I.
Orho‐Melander, M.
Franco‐Cereceda, A.
Borén, J.
Eriksson, P.
Magné, J.
Parini, P.
Ehrenborg, E.
Subclinical atherosclerosis and its progression are modulated by PLIN2 through a feed‐forward loop between LXR and autophagy
title Subclinical atherosclerosis and its progression are modulated by PLIN2 through a feed‐forward loop between LXR and autophagy
title_full Subclinical atherosclerosis and its progression are modulated by PLIN2 through a feed‐forward loop between LXR and autophagy
title_fullStr Subclinical atherosclerosis and its progression are modulated by PLIN2 through a feed‐forward loop between LXR and autophagy
title_full_unstemmed Subclinical atherosclerosis and its progression are modulated by PLIN2 through a feed‐forward loop between LXR and autophagy
title_short Subclinical atherosclerosis and its progression are modulated by PLIN2 through a feed‐forward loop between LXR and autophagy
title_sort subclinical atherosclerosis and its progression are modulated by plin2 through a feed‐forward loop between lxr and autophagy
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6899829/
https://www.ncbi.nlm.nih.gov/pubmed/31251843
http://dx.doi.org/10.1111/joim.12951
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