Atherosclerosis

2019

DOI: 10.1016/j.atherosclerosis.2019.06.132

|View full text |Cite

|

Sign up to set email alerts

|

Macrophage Atp-Citrate Lyase (Acly) Deficiency Affects Cellular Cholesterol Homeostasis And Stabilizes Atherosclerotic Lesions

Jeroen Baardman

¹

,

Saskia van der Velden

²

,

³

et al.

Help me understand this report

Search citation statements

Order By: Relevance

Paper Sections

Select...

Introduction2

Discussion1

Acly Exerts Inhibitory Effects On Proinflammatory Cytokine E...1

Metabolic Reprogramming In Macrophages1

Citation Types

Supporting

1

Mentioning

8

Contrasting

0

Year Published

2021

2021

2023

2023

Publication Types

Select...

Article3

Preprint1

Relationship

Self Cite0

Independent4

Authors

Journals

Cited by 4 publications

(9 citation statements)

References 0 publications

Supporting

1

Mentioning

8

Contrasting

0

Order By: Relevance

“…Our study highlights that THP-1 cells with impaired ACLY activity have a hyperinflammatory gene signature when exposed to LPS. This phenomenon has recently been described in murine BMDMs in vitro and in vivo (14,15). Surprisingly, we did not find differences in the expression of cholesterol handling or efflux genes observed in BMDMs, which may be due to interspecies or cell line differences.…”

Section: Discussionmentioning

confidence: 64%

“…Interestingly, in contrast to global decreases of histone H3 K27 acetylation, chromatin immunoprecipitation (ChIP) experiments revealed a tendency to increased association of K27-acetylated histone H3 with promoters of CCL2 and CCL4 (Figure 2E) in ACLY knockout THP-1 cells. ACLY knockout murine bone marrow-derived macrophages (BMDMs) showed up-regulation of several genes related to cholesterol synthesis and efflux (14). On the contrary, mRNA expression of cholesterol handling genes such as ABCG1, ABCA1, FASN or DHCR24 was not significantly altered in our cell lines (Supplementary Figure 4).…”

Section: Acly Exerts Inhibitory Effects On Proinflammatory Cytokine E...mentioning

confidence: 75%

“…By re-expressing wild type, catalytically inactive H760A, and phosphorylation-deficient S455A ACLY mutants, we showed that basal ACLY serine 455 phosphorylation does not influence enzymatic ACLY function in THP-1 cells. Moreover, attenuating ACLY in THP-1 cells showed a pro-inflammatory phenotype similar to that of knockout BMDMs (14), an effect not recapitulated by pharmacological inhibition of ACLY.…”

Section: Introductionmentioning

confidence: 92%

“…Thus, in murine macrophages, pharmacological ACLY inhibition or ACLY silencing decreased histone acetylation and reduced pro-inflammatory gene expression after stimulation with lipopolysaccharide (LPS) (12,13). In contrast, recent in vivo and in vitro studies of myeloid-specific ACLY deficiency reported increased pro-inflammatory gene expression in macrophages and atherosclerotic plaques (14,15). While the effects of ACLY on murine macrophage pro-inflammatory or alternative polarization have recently been described both in vitro and in vivo, we are still uncertain of the effects ACLY exhibits in human macrophages.…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Impact of ATP-citrate lyase catalytic activity and serine 455 phosphorylation on histone acetylation and inflammatory responses in human monocytic THP-1 cells

¹

,

²

,

³

et al. 2022

Front. Immunol.

View full text Add to dashboard Cite

ATP-citrate lyase (ACLY) is a key enzyme provoking metabolic and epigenetic gene regulation. Molecularly, these functions are exerted by the provision of acetyl-coenzyme A, which is then used as a substrate for de novo lipogenesis or as an acetyl-group donor in acetylation reactions. It has been demonstrated that ACLY activity can be positively regulated via phosphorylation at serine 455 by Akt and protein kinase A. Nonetheless, the impact of phosphorylation on ACLY function in human myeloid cells is poorly understood. In this study we reconstituted ACLY knockout human monocytic THP-1 cells with a wild type ACLY as well as catalytically inactive H760A, and phosphorylation-deficient S455A mutants. Using these cell lines, we determined the impact of ACLY activity and phosphorylation on histone acetylation and pro-inflammatory gene expression in response to lipopolysaccharide (LPS). Our results show that ACLY serine 455 phosphorylation does not influence the proper enzymatic function of ACLY, since both, wild type ACLY and phosphorylation-deficient mutant, exhibited increased cell growth and histone acetylation as compared to cells with a loss of ACLY activity. Transcriptome analysis revealed enhanced expression of pro-inflammatory and interferon response genes in ACLY knockout and H760A THP-1 cells under unstimulated or LPS-treated conditions. At the same time, S455A ACLY-expressing cells showed a phenotype very similar to wild type cells. Contrary to ACLY knockout, pharmacological inhibition of ACLY in THP-1 cells or in primary human macrophages does not enhance LPS-triggered pro-inflammatory gene expression. Our data thus suggest that ACLY retains functionality in the absence of Akt/PKA-mediated phosphorylation in human myeloid cells. Furthermore, loss of ACLY activity may elicit long-term adaptive mechanisms, increasing inflammatory responses.

“…Our study highlights that THP-1 cells with impaired ACLY activity have a hyperinflammatory gene signature when exposed to LPS. This phenomenon has recently been described in murine BMDMs in vitro and in vivo (14,15). Surprisingly, we did not find differences in the expression of cholesterol handling or efflux genes observed in BMDMs, which may be due to interspecies or cell line differences.…”

Section: Discussionmentioning

confidence: 64%

“…Interestingly, in contrast to global decreases of histone H3 K27 acetylation, chromatin immunoprecipitation (ChIP) experiments revealed a tendency to increased association of K27-acetylated histone H3 with promoters of CCL2 and CCL4 (Figure 2E) in ACLY knockout THP-1 cells. ACLY knockout murine bone marrow-derived macrophages (BMDMs) showed up-regulation of several genes related to cholesterol synthesis and efflux (14). On the contrary, mRNA expression of cholesterol handling genes such as ABCG1, ABCA1, FASN or DHCR24 was not significantly altered in our cell lines (Supplementary Figure 4).…”

Section: Acly Exerts Inhibitory Effects On Proinflammatory Cytokine E...mentioning

confidence: 75%

“…By re-expressing wild type, catalytically inactive H760A, and phosphorylation-deficient S455A ACLY mutants, we showed that basal ACLY serine 455 phosphorylation does not influence enzymatic ACLY function in THP-1 cells. Moreover, attenuating ACLY in THP-1 cells showed a pro-inflammatory phenotype similar to that of knockout BMDMs (14), an effect not recapitulated by pharmacological inhibition of ACLY.…”

Section: Introductionmentioning

confidence: 92%

“…Thus, in murine macrophages, pharmacological ACLY inhibition or ACLY silencing decreased histone acetylation and reduced pro-inflammatory gene expression after stimulation with lipopolysaccharide (LPS) (12,13). In contrast, recent in vivo and in vitro studies of myeloid-specific ACLY deficiency reported increased pro-inflammatory gene expression in macrophages and atherosclerotic plaques (14,15). While the effects of ACLY on murine macrophage pro-inflammatory or alternative polarization have recently been described both in vitro and in vivo, we are still uncertain of the effects ACLY exhibits in human macrophages.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Impact of ATP-citrate lyase catalytic activity and serine 455 phosphorylation on histone acetylation and inflammatory responses in human monocytic THP-1 cells

¹

,

²

,

³

et al. 2022

Front. Immunol.

View full text Add to dashboard Cite

ATP-citrate lyase (ACLY) is a key enzyme provoking metabolic and epigenetic gene regulation. Molecularly, these functions are exerted by the provision of acetyl-coenzyme A, which is then used as a substrate for de novo lipogenesis or as an acetyl-group donor in acetylation reactions. It has been demonstrated that ACLY activity can be positively regulated via phosphorylation at serine 455 by Akt and protein kinase A. Nonetheless, the impact of phosphorylation on ACLY function in human myeloid cells is poorly understood. In this study we reconstituted ACLY knockout human monocytic THP-1 cells with a wild type ACLY as well as catalytically inactive H760A, and phosphorylation-deficient S455A mutants. Using these cell lines, we determined the impact of ACLY activity and phosphorylation on histone acetylation and pro-inflammatory gene expression in response to lipopolysaccharide (LPS). Our results show that ACLY serine 455 phosphorylation does not influence the proper enzymatic function of ACLY, since both, wild type ACLY and phosphorylation-deficient mutant, exhibited increased cell growth and histone acetylation as compared to cells with a loss of ACLY activity. Transcriptome analysis revealed enhanced expression of pro-inflammatory and interferon response genes in ACLY knockout and H760A THP-1 cells under unstimulated or LPS-treated conditions. At the same time, S455A ACLY-expressing cells showed a phenotype very similar to wild type cells. Contrary to ACLY knockout, pharmacological inhibition of ACLY in THP-1 cells or in primary human macrophages does not enhance LPS-triggered pro-inflammatory gene expression. Our data thus suggest that ACLY retains functionality in the absence of Akt/PKA-mediated phosphorylation in human myeloid cells. Furthermore, loss of ACLY activity may elicit long-term adaptive mechanisms, increasing inflammatory responses.

“…Lipid biosynthesis is essential for membrane remodelling and in M1 macrophages the process depends on the production of acetyl-CoA from citrate ATP-citrate lyase (ACLY) (86).…”

Section: Metabolic Reprogramming In Macrophagesmentioning

confidence: 99%

Redox Regulation of the Immune Response: Nitro-Oxidative Stress and Antioxidants Regulate Macrophage, Neutrophil, and T and B Lymphocyte, and Dendritic and Natural Killer Cell Functions

2021

Preprint

View full text Add to dashboard Cite

An immune-inflammatory response is accompanied by increased nitro-oxidative stress. The aims of this mechanistic review are to review: a) the role of redox sensitive transcription factors and enzymes, ROS/RNS production and the activity of cellular antioxidants on the activation and performance of macrophages, dendritic cells, neutrophils, T cells, B cells and natural killer cells; b) the involvement of high-density lipoprotein (HDL), apolipoprotein (Apo)A1, paraoxonase (PON)-1, and oxidized phospholipids in the regulation of the immune response; and c) the detrimental effects of hypernitrosylation and chronic nitro-oxidative stress on the immune response. The redox changes during immune-inflammatory responses are orchestrated by the actions of nuclear factor (NF)-κB, HIF1alpha, the mechanistic target of rapamycin (mTor), the phosphatidylinositol 3‑kinase (PI3K) / protein kinase B (AKT) signalling pathway, mitogen-activated protein (MAP) kinases, 5' AMP-activated protein kinase (AMPK), and peroxisome proliferator-activated receptor (PPAR). The performance and survival of individual immune cells is under redox control and sensitive to intracellular and extracellular levels of ROS/RNS and is heavily influenced by cellular anti-oxidants including the glutathione and thioredoxin systems, nuclear factor erythroid 2-related factor 2 (Nrf-2), and the HDL complex. Chronic nitro-oxidative stress and hypernitrosylation inhibit the activity of those antioxidant systems, the tricarboxylic acid cycle, mitochondrial functions, and the metabolism of immune cells. In conclusion, those redox-associated mechanisms modulate metabolic reprogramming of immune cells, macrophage and T helper cell polarization, phagocytosis, production of pro- versus anti-inflammatory cytokines, immune training and tolerance, chemotaxis, pathogen sensing, antiviral and antibacterial effects, Toll-like receptor activity, and endotoxin tolerance.

Novel insights into the role of acetyl-CoA producing enzymes in epigenetic regulation

Russo,

Pileri,

Ghisletti

2023

Front. Endocrinol.

View full text Add to dashboard Cite

Inflammation-dependent changes in gene expression programs in innate immune cells, such as macrophages, involve extensive reprogramming of metabolism. This reprogramming is essential for the production of metabolites required for chromatin modifications, such as acetyl-CoA, and regulate their usage and availability impacting the macrophage epigenome. One of the most transcriptionally induced proinflammatory mediator is nitric oxide (NO), which has been shown to inhibit key metabolic enzymes involved in the production of these metabolites. Recent evidence indicates that NO inhibits mitochondrial enzymes such as pyruvate dehydrogenase (PDH) in macrophages induced by inflammatory stimulus. PDH is involved in the production of acetyl-CoA, which is essential for chromatin modifications in the nucleus, such as histone acetylation. In addition, acetyl-CoA levels in inflamed macrophages are regulated by ATP citrate lyase (ACLY) and citrate transporter SLC25A1. Interestingly, acetyl-CoA producing enzymes, such as PDH and ACLY, have also been reported to be present in the nucleus and to support the local generation of cofactors such as acetyl-CoA. Here, we will discuss the mechanisms involved in the regulation of acetyl-CoA production by metabolic enzymes, their inhibition by prolonged exposure to inflammation stimuli, their involvement in dynamic inflammatory expression changes and how these emerging findings could have significant implications for the design of novel therapeutic approaches.

scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.

Contact Info

hi@scite.ai

10624 S. Eastern Ave., Ste. A-614

Henderson, NV 89052, USA

Product

Browser Extension Assistant by scite Citation Statement Search Reference Check Visualizations Dashboards Explore Journals Explore Organizations Explore Funders Embedding Badge Embedding Citation Search Pricing

Resources

Blog Help & FAQ Accessibility Statement API Terms For Universities & Governments For Researchers For Publishers For Corporate, Pharma & Enterprise Author Marketing Become an Affiliate Get an organization trial or quote scite Data & Services

About

News & Press Careers Read our Paper Coverage

Blog Terms and Conditions API Terms Privacy Policy Contact Cookie Preferences Do Not Sell or Share My Personal Information

Copyright © 2024 scite LLC. All rights reserved.

Made with 💙 for researchers

Part of the Research Solutions Family.