Macrophage ATP citrate lyase deficiency stabilizes atherosclerotic plaques

Jeroen Baardman; Sanne G.S. Verberk; Saskia van der Velden; Marion J.J. Gijbels; Cindy P.P.A. van Roomen; Judith C. Sluimer; Jelle Y. Broos; Guillermo R. Griffith; Koen H.M. Prange; Michel van Weeghel; Soufyan Lakbir; Douwe Molenaar; Elisa Meinster; Annette E. Neele; Gijs Kooij; Helga E. de Vries; Esther Lutgens; Kathryn E. Wellen; Menno P.J. de Winther; Jan Van den Bossche

doi:10.1038/s41467-020-20141-z

Macrophage ATP citrate lyase deficiency stabilizes atherosclerotic plaques

Jeroen Baardman, Sanne G.S. Verberk, Saskia van der Velden, Marion J.J. Gijbels, Cindy P.P.A. van Roomen, Judith C. Sluimer, Jelle Y. Broos, Guillermo R. Griffith, Koen H.M. Prange, Michel van Weeghel, Soufyan Lakbir, Douwe Molenaar, Elisa Meinster, Annette E. Neele, Gijs Kooij, Helga E. de Vries, Esther Lutgens, Kathryn E. Wellen, Menno P.J. de Winther^*, Jan Van den Bossche^*

^*Corresponding author for this work

Vrije Universiteit Amsterdam

Research output: Contribution to journal › Article › Academic › peer-review

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.

Original language	English
Article number	6296
Journal	Nature Communications
Volume	11
DOIs	https://doi.org/10.1038/s41467-020-20141-z
Publication status	Published - Dec 2020
Externally published	Yes

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Baardman, J., Verberk, S. G. S., van der Velden, S., Gijbels, M. J. J., van Roomen, C. P. P. A., Sluimer, J. C., Broos, J. Y., Griffith, G. R., Prange, K. H. M., van Weeghel, M., Lakbir, S., Molenaar, D., Meinster, E., Neele, A. E., Kooij, G., de Vries, H. E., Lutgens, E., Wellen, K. E., de Winther, M. P. J., & den Bossche, J. V. (2020). Macrophage ATP citrate lyase deficiency stabilizes atherosclerotic plaques. Nature Communications, 11, Article 6296. https://doi.org/10.1038/s41467-020-20141-z

@article{0ab4e3237c9c4cb98d8fce3c2801581a,

title = "Macrophage ATP citrate lyase deficiency stabilizes atherosclerotic plaques",

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.",

author = "Jeroen Baardman and Verberk, {Sanne G.S.} and {van der Velden}, Saskia and Gijbels, {Marion J.J.} and {van Roomen}, {Cindy P.P.A.} and Sluimer, {Judith C.} and Broos, {Jelle Y.} and Griffith, {Guillermo R.} and Prange, {Koen H.M.} and {van Weeghel}, Michel and Soufyan Lakbir and Douwe Molenaar and Elisa Meinster and Neele, {Annette E.} and Gijs Kooij and {de Vries}, {Helga E.} and Esther Lutgens and Wellen, {Kathryn E.} and {de Winther}, {Menno P.J.} and {den Bossche}, {Jan Van}",

year = "2020",

month = dec,

doi = "10.1038/s41467-020-20141-z",

language = "English",

volume = "11",

journal = "Nature Communications",

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publisher = "Nature Research",

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Baardman, J, Verberk, SGS, van der Velden, S, Gijbels, MJJ, van Roomen, CPPA, Sluimer, JC, Broos, JY, Griffith, GR, Prange, KHM, van Weeghel, M, Lakbir, S, Molenaar, D, Meinster, E, Neele, AE, Kooij, G, de Vries, HE, Lutgens, E, Wellen, KE, de Winther, MPJ & den Bossche, JV 2020, 'Macrophage ATP citrate lyase deficiency stabilizes atherosclerotic plaques', Nature Communications, vol. 11, 6296. https://doi.org/10.1038/s41467-020-20141-z

TY - JOUR

T1 - Macrophage ATP citrate lyase deficiency stabilizes atherosclerotic plaques

AU - Baardman, Jeroen

AU - Verberk, Sanne G.S.

AU - van der Velden, Saskia

AU - Gijbels, Marion J.J.

AU - van Roomen, Cindy P.P.A.

AU - Sluimer, Judith C.

AU - Broos, Jelle Y.

AU - Griffith, Guillermo R.

AU - Prange, Koen H.M.

AU - van Weeghel, Michel

AU - Lakbir, Soufyan

AU - Molenaar, Douwe

AU - Meinster, Elisa

AU - Neele, Annette E.

AU - Kooij, Gijs

AU - de Vries, Helga E.

AU - Lutgens, Esther

AU - Wellen, Kathryn E.

AU - de Winther, Menno P.J.

AU - den Bossche, Jan Van

PY - 2020/12

Y1 - 2020/12

N2 - 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.

AB - 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.

UR - https://research.vu.nl/en/publications/b904c5ba-d7f2-473f-9e15-0621838f34e2

U2 - 10.1038/s41467-020-20141-z

DO - 10.1038/s41467-020-20141-z

M3 - Article

C2 - 33293558

SN - 2041-1723

VL - 11

JO - Nature Communications

JF - Nature Communications

M1 - 6296

ER -

Macrophage ATP citrate lyase deficiency stabilizes atherosclerotic plaques

Abstract

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