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

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MARC

Saliba-Gustafsson, P.Karolinska Institute,Karolinska Institutet,Stanford University,Karolinska University Hospital (author)

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

Article/chapterEnglish2019

Publisher, publication year, extent ...

2019-07-29
Wiley,2019

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LIBRIS-ID:oai:gup.ub.gu.se/282972
https://gup.ub.gu.se/publication/282972URI
https://doi.org/10.1111/joim.12951DOI
http://kipublications.ki.se/Default.aspx?queryparsed=id:141456399URI
https://lup.lub.lu.se/record/95c10b9c-1e9f-44a3-bc04-d77fe96b5c78URI

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Language:English

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SwePubSwePub

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Subject category:ref swepub-contenttype
Subject category:art swepub-publicationtype

Notes

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.

Subject headings and genre

MEDICIN OCH HÄLSOVETENSKAP Klinisk medicin Kardiologi hsv//swe
MEDICAL AND HEALTH SCIENCES Clinical Medicine Cardiac and Cardiovascular Systems hsv//eng
27OH-cholesterol
atherosclerosis
autophagy
liver-X-receptor
PLIN2
reverse cholesterol transport
macrophage foam cells
accumulation
efflux
identification
stimulation
metabolism
receptors
ser251pro
protects
General & Internal Medicine

Added entries (persons, corporate bodies, meetings, titles ...)

Pedrelli, M.Karolinska Institute,Karolinska Institutet (author)
Gertow, K.Karolinska Institute,Karolinska University Hospital (author)
Werngren, O.Karolinska Institute,Karolinska University Hospital (author)
Janas, V.Karolinska Institute,Karolinska University Hospital (author)
Pourteymour, S. (author)
Baldassarre, D.Centro Cardiologico Monzino,University of Milan (author)
Tremoli, E.Centro Cardiologico Monzino,University of Milan (author)
Veglia, F.Centro Cardiologico Monzino (author)
Rauramaa, R.University of Eastern Finland (author)
Smit, A. J.University Medical Center Groningen (author)
Giral, P.Pitié-Salpêtrière University Hospital (author)
Kurl, S.University of Eastern Finland (author)
Pirro, M.University of Perugia (author)
de Faire, U.Karolinska Institute,Karolinska Institutet (author)
Humphries, S. E.Karolinska Institute,Karolinska Institutet,University College London,Karolinska University Hospital (author)
Hamsten, A.Karolinska Institute,Karolinska Institutet,Karolinska University Hospital (author)
Gonçalves, I.Lund University,Lunds universitet,Kardiovaskulär forskning - translationella studier,Forskargrupper vid Lunds universitet,Cardiovascular Research - Translational Studies,Lund University Research Groups(Swepub:lu)medf-igo (author)
Orho-Melander, M.Lund University,Lunds universitet,Diabetes - kardiovaskulär sjukdom,Forskargrupper vid Lunds universitet,Diabetes - Cardiovascular Disease,Lund University Research Groups(Swepub:lu)endo-mor (author)
Franco-Cereceda, A.Karolinska Institute,Karolinska Institutet,Karolinska University Hospital (author)
Borén, Jan,1963University of Gothenburg,Gothenburg University,Göteborgs universitet,Institutionen för medicin, avdelningen för molekylär och klinisk medicin,Wallenberglaboratoriet,Institute of Medicine, Department of Molecular and Clinical Medicine,Wallenberg Laboratory,Sahlgrenska University Hospital(Swepub:gu)xborej (author)
Eriksson, P.Karolinska Institute,Karolinska Institutet,Karolinska University Hospital (author)
Magne, J.Karolinska Institute,Karolinska Institutet,St Jude Children´s Research Hospital, Memphis,Karolinska University Hospital (author)
Parini, P. (author)
Ehrenborg, E. (author)
Sirtori, C. R. (author)
Castelnuovo, S. (author)
Amato, M. (author)
Frigerio, B. (author)
Ravani, A. (author)
Sansaro, D. (author)
Tedesco, C. (author)
Bovis, F. (author)
Discacciati, A. (author)
Ahl, M. (author)
Blomgren, G. (author)
Eriksson, M. J. (author)
Fahlstadius, P. (author)
Heinonen, M. (author)
Nilson, L. (author)
Cooper, J. (author)
Acharya, J. (author)
Huttunen, K. (author)
Rauramaa, E. (author)
Pekkarinen, H. (author)
Penttila, I. M. (author)
Torronen, J. (author)
van Gessel, A. I. (author)
van Roon, A. M. (author)
Teune, G. C. (author)
Kuipers, W. D. (author)
Bruin, M. (author)
Nicolai, A. (author)
Haarsma-Jorritsma, P. (author)
Mulder, D. J. (author)
Bilo, H. J. G. (author)
Smeets, G. H. (author)
Beaudeux, J. L. (author)
Kahn, J. F. (author)
Carreau, V. (author)
Kontush, A. (author)
Karppi, J. (author)
Nurmi, T. (author)
Nyyssonen, K. (author)
Salonen, R. (author)
Tuomainen, T. P. (author)
Tuomainen, J. (author)
Kauhanen, J. (author)
Vaudo, G. (author)
Alaeddin, A. (author)
Siepi, D. (author)
Lupattelli, G. (author)
Schillaci, G. (author)
Karolinska InstituteKarolinska Institutet (creator_code:org_t)

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In:Journal of Internal Medicine: Wiley286:6, s. 660-6750954-68201365-2796

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By the author/editor: Saliba-Gustafsso ...; Pedrelli, M.; Gertow, K.; Werngren, O.; Janas, V.; Pourteymour, S.; show more...; 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, ...; Borén, Jan, 1963; Eriksson, P.; Magne, J.; Parini, P.; Ehrenborg, E.; Sirtori, C. R.; Castelnuovo, S.; Amato, M.; Frigerio, B.; Ravani, A.; Sansaro, D.; Tedesco, C.; Bovis, F.; Discacciati, A.; Ahl, M.; Blomgren, G.; Eriksson, M. J.; Fahlstadius, P.; Heinonen, M.; Nilson, L.; Cooper, J.; Acharya, J.; Huttunen, K.; Rauramaa, E.; Pekkarinen, H.; Penttila, I. M.; Torronen, J.; van Gessel, A. I ...; van Roon, A. M.; Teune, G. C.; Kuipers, W. D.; Bruin, M.; Nicolai, A.; Haarsma-Jorritsm ...; Mulder, D. J.; Bilo, H. J. G.; Smeets, G. H.; Beaudeux, J. L.; Kahn, J. F.; Carreau, V.; Kontush, A.; Karppi, J.; Nurmi, T.; Nyyssonen, K.; Salonen, R.; Tuomainen, T. P.; Tuomainen, J.; Kauhanen, J.; Vaudo, G.; Alaeddin, A.; Siepi, D.; Lupattelli, G.; Schillaci, G.; show less...

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MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Clinical Medicin ...; and Cardiac and Card ...

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