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 g...
| Main Authors: | , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2023-07-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-023-05932-8 |
| _version_ | 1797784351836995584 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Ranran Li |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-13T00:38:39Z |
| format | Article |
| id | doaj.art-51b8efe7d13b419e8701005c2f4b9372 |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-03-13T00:38:39Z |
| publishDate | 2023-07-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-51b8efe7d13b419e8701005c2f4b93722023-07-09T11:26:31ZengNature Publishing GroupCell Death and Disease2041-48892023-07-0114711410.1038/s41419-023-05932-8ATP-citrate lyase controls endothelial gluco-lipogenic metabolism and vascular inflammation in sepsis-associated organ injuryRanran Li0Mei Meng1Ying Chen2Tingting Pan3Yinjiaozhi Li4Yunxin Deng5Ruyuan Zhang6Rui Tian7Wen Xu8Xiangtao Zheng9Fangchen Gong10Jie Liu11Haiting Tang12Xiaowei Ding13Yaoqing Tang14Djillali Annane15Erzhen Chen16Hongping Qu17Lei Li18Department of Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of MedicineDepartment of Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of MedicineDepartment of Emergency, Ruijin Hospital, Shanghai Jiao Tong University School of MedicineDepartment of Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of MedicineDepartment of Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of MedicineDepartment of Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of MedicineDepartment of Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of MedicineDepartment of Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of MedicineDepartment of Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of MedicineDepartment of Emergency, Ruijin Hospital, Shanghai Jiao Tong University School of MedicineDepartment of Emergency, Ruijin Hospital, Shanghai Jiao Tong University School of MedicineNational Advanced Medical Engineering Research Center, China State Institute of Pharmaceutical IndustryDepartment of Obstetrics and Gynecology, Ruijin Hospital, Shanghai Jiao Tong University School of MedicineDepartment of Obstetrics and Gynecology, Ruijin Hospital, Shanghai Jiao Tong University School of MedicineDepartment of Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of MedicineGeneral intensive care unit, Raymond Poincaré Hospital (APHP), Laboratory of Inflammation and Infection U1173, University of Versailles SQY/INSERM 104 bd Raymond PoincaréDepartment of Emergency, Ruijin Hospital, Shanghai Jiao Tong University School of MedicineDepartment of Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of MedicineDepartment of Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of MedicineAbstract 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.https://doi.org/10.1038/s41419-023-05932-8 |
| spellingShingle | 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 ATP-citrate lyase controls endothelial gluco-lipogenic metabolism and vascular inflammation in sepsis-associated organ injury Cell Death and Disease |
| title | ATP-citrate lyase controls endothelial gluco-lipogenic metabolism and vascular inflammation in sepsis-associated organ injury |
| title_full | ATP-citrate lyase controls endothelial gluco-lipogenic metabolism and vascular inflammation in sepsis-associated organ injury |
| title_fullStr | ATP-citrate lyase controls endothelial gluco-lipogenic metabolism and vascular inflammation in sepsis-associated organ injury |
| title_full_unstemmed | ATP-citrate lyase controls endothelial gluco-lipogenic metabolism and vascular inflammation in sepsis-associated organ injury |
| title_short | ATP-citrate lyase controls endothelial gluco-lipogenic metabolism and vascular inflammation in sepsis-associated organ injury |
| title_sort | atp citrate lyase controls endothelial gluco lipogenic metabolism and vascular inflammation in sepsis associated organ injury |
| url | https://doi.org/10.1038/s41419-023-05932-8 |
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