ATP-citrate lyase controls endothelial gluco-lipogenic metabolism and vascular inflammation in sepsis-associated organ injury.

Abstract

Sepsis involves endothelial cell (EC) dysfunction, which contributes to multiple organ failure. To improve therapeutic prospects, elucidating molecular mechanisms of vascular dysfunction is of the essence. ATP-citrate lyase (ACLY) directs glucose metabolic fluxes to de novo lipogenesis by generating acetyl-Co-enzyme A (acetyl-CoA), which facilitates transcriptional priming via protein acetylation. It is well illustrated that ACLY participates in promoting cancer metastasis and fatty liver diseases. Its biological functions in ECs during sepsis remain unclear. We found that plasma levels of ACLY were increased in septic patients and were positively correlated with interleukin (IL)-6, soluble E-selectin (sE-selectin), soluble vascular cell adhesion molecule 1 (sVCAM-1), and lactate levels. ACLY inhibition significantly ameliorated lipopolysaccharide challenge-induced EC proinflammatory response in vitro and organ injury in vivo. The metabolomic analysis revealed that ACLY blockade fostered ECs a quiescent status by reducing the levels of glycolytic and lipogenic metabolites. Mechanistically, ACLY promoted forkhead box O1 (FoxO1) and histone H3 acetylation, thereby increasing the transcription of c-Myc (MYC) to facilitate the expression of proinflammatory and gluco-lipogenic genes. Our findings revealed that ACLY promoted EC gluco-lipogenic metabolism and proinflammatory response through acetylation-mediated MYC transcription, suggesting ACLY as the potential therapeutic target for treating sepsis-associated EC dysfunction and organ injury.

• Authors: Ranran Li, Mei Meng, Ying Chen, Tingting Pan, Yinjiaozhi Li, Yunxin Deng, Ruyuan Zhang, Rui Tian, Wen Xu, Xiangtao Zheng, Fangchen Gong, Jie Liu, Haiting Tang, Xiaowei Ding, Yaoqing Tang, Djillali Annane, Erzhen Chen, Hongping Qu, Lei Li
• Journal: Cell death & disease (Cell Death Dis) Vol. 14 Issue 7 Pg. 401 (07 06 2023) ISSN: 2041-4889 [Electronic] England
• PMID: 37414769 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2023. The Author(s).

Chemical References

• ATP Citrate (pro-S)-Lyase
• citrate (pro-3S)-lyase
• Adenosine Triphosphate

Topics

• Humans
• Lipogenesis
• ATP Citrate (pro-S)-Lyase (metabolism)
• Inflammation
• Adenosine Triphosphate (metabolism)