Macrophage ATP citrate lyase deficiency stabilizes atherosclerotic plaques

Macrophages represent a major immune cell population in atherosclerotic plaques and play central role in the progression of this lipid-driven chronic inflammatory disease. Targeting immunometabolism is proposed as a strategy to revert aberrant macrophage activation to improve disease outcome. Here,...

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Vydané v:	Nature communications Ročník 11; číslo 1; s. 6296 - 15
Hlavní autori:	Baardman, Jeroen, Verberk, Sanne G. S., van der Velden, Saskia, Gijbels, Marion J. J., van Roomen, Cindy P. P. A., Sluimer, Judith C., Broos, Jelle Y., Griffith, Guillermo R., Prange, Koen H. M., van Weeghel, Michel, Lakbir, Soufyan, Molenaar, Douwe, Meinster, Elisa, Neele, Annette E., Kooij, Gijs, de Vries, Helga E., Lutgens, Esther, Wellen, Kathryn E., de Winther, Menno P. J., Van den Bossche, Jan
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	London Nature Publishing Group UK 08.12.2020 Nature Publishing Group Nature Portfolio
Predmet:	101/58 13/2 13/21 13/31 13/51 14 14/1 38 38/88 38/91 45 631/250/2504/342 64/60 692/699/75 Aged Animals Apoptosis Apoptosis - immunology Arteriosclerosis Atherosclerosis ATP Citrate (pro-S)-Lyase - antagonists & inhibitors ATP Citrate (pro-S)-Lyase - deficiency ATP Citrate (pro-S)-Lyase - genetics ATP citrate lyase Biosynthesis Cell activation Cholesterol Cholesterol - biosynthesis Collagen Collagen - metabolism Deregulation Diet, High-Fat - adverse effects Disease Models, Animal Dyslipidemia Fatty acids Fatty Acids - biosynthesis Female Fibrosis Gene Expression Profiling Humanities and Social Sciences Humans Immune system Inflammatory diseases Lipidomics Lipids Lipogenesis - immunology Liver X receptors Liver X Receptors - metabolism Macrophage Activation Macrophages Macrophages - immunology Macrophages - metabolism Male Mice, Knockout multidisciplinary Necrosis - immunology Necrosis - pathology Phagocytosis Phenotypes Plaque, Atherosclerotic - drug therapy Plaque, Atherosclerotic - immunology Plaque, Atherosclerotic - pathology Plaques Receptor mechanisms Science Science (multidisciplinary) Transcription
ISSN:	2041-1723, 2041-1723
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Shrnutí:	Macrophages represent a major immune cell population in atherosclerotic plaques and play central role in the progression of this lipid-driven chronic inflammatory disease. Targeting immunometabolism is proposed as a strategy to revert aberrant macrophage activation to improve disease outcome. Here, we show ATP citrate lyase (Acly) to be activated in inflammatory macrophages and human atherosclerotic plaques. We demonstrate that myeloid Acly deficiency induces a stable plaque phenotype characterized by increased collagen deposition and fibrous cap thickness, along with a smaller necrotic core. In-depth functional, lipidomic, and transcriptional characterization indicate deregulated fatty acid and cholesterol biosynthesis and reduced liver X receptor activation within the macrophages in vitro. This results in macrophages that are more prone to undergo apoptosis, whilst maintaining their capacity to phagocytose apoptotic cells. Together, our results indicate that targeting macrophage metabolism improves atherosclerosis outcome and we reveal Acly as a promising therapeutic target to stabilize atherosclerotic plaques. Inhibition of the metabolic enzyme ATP-citrate lyase can attenuate atherosclerosis by preventing dyslipidemia and potentially also by reducing macrophage-mediated inflammation. Here, the authors show that specific targeting of ACLY in macrophages results in more stable atherosclerotic plaques.
Bibliografia:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	2041-1723 2041-1723
DOI:	10.1038/s41467-020-20141-z