Macrophage ATP citrate lyase deficiency stabilizes atherosclerotic plaques

Jeroen Baardman, Sanne G. S. Verberk, Saskia Velden, Marion J. J. Gijbels, Cindy P. P. A. Roomen, Judith C. Sluimer, Jelle Y. Broos, Guillermo R. Griffith, Koen H. M. Prange, Michel Weeghel, Soufyan Lakbir, Douwe Molenaar, Elisa Meinster, Annette E. Neele, Gijs Kooij, Helga E. Vries, Esther Lutgens, Kathryn E. Wellen, Menno P. J. Winther () and Jan Bossche ()
Additional contact information
Jeroen Baardman: Amsterdam UMC, University of Amsterdam
Sanne G. S. Verberk: Amsterdam UMC, Vrije Universiteit Amsterdam
Saskia Velden: Amsterdam UMC, University of Amsterdam
Marion J. J. Gijbels: Amsterdam UMC, University of Amsterdam
Cindy P. P. A. Roomen: Amsterdam UMC, University of Amsterdam
Judith C. Sluimer: CARIM, Maastricht University
Jelle Y. Broos: Amsterdam UMC, Vrije Universiteit Amsterdam
Guillermo R. Griffith: Amsterdam UMC, University of Amsterdam
Koen H. M. Prange: Amsterdam UMC, University of Amsterdam
Michel Weeghel: Amsterdam UMC, University of Amsterdam
Soufyan Lakbir: Amsterdam UMC, Vrije Universiteit Amsterdam
Douwe Molenaar: Vrije Universiteit Amsterdam
Elisa Meinster: Amsterdam UMC, Vrije Universiteit Amsterdam
Annette E. Neele: Amsterdam UMC, University of Amsterdam
Gijs Kooij: Amsterdam UMC, Vrije Universiteit Amsterdam
Helga E. Vries: Amsterdam UMC, Vrije Universiteit Amsterdam
Esther Lutgens: Amsterdam UMC, University of Amsterdam
Kathryn E. Wellen: University of Pennsylvania
Menno P. J. Winther: Amsterdam UMC, University of Amsterdam
Jan Bossche: Amsterdam UMC, University of Amsterdam

Nature Communications, 2020, vol. 11, issue 1, 1-15

Abstract: Abstract 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.

Date: 2020
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DOI: 10.1038/s41467-020-20141-z

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