Department of Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China.
Department of Emergency, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China.
Cell Death Dis. 2023 Jul 6;14(7):401. doi: 10.1038/s41419-023-05932-8.
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.
败血症涉及内皮细胞（EC）功能障碍，这导致多器官衰竭。为了改善治疗前景，阐明血管功能障碍的分子机制至关重要。ATP-柠檬酸裂解酶（ACLY）通过生成乙酰辅酶 A（acetyl-CoA）将葡萄糖代谢通量引导至从头脂肪生成，从而通过蛋白质乙酰化促进转录起始。已经充分说明了 ACLY 参与促进癌症转移和脂肪肝疾病。在败血症中，其在 EC 中的生物学功能尚不清楚。我们发现败血症患者的血浆 ACLY 水平升高，并且与白细胞介素（IL）-6、可溶性 E-选择素（sE-选择素）、可溶性血管细胞黏附分子 1（sVCAM-1）和乳酸水平呈正相关。ACLY 抑制显著改善了体外脂多糖刺激引起的 EC 促炎反应和体内器官损伤。代谢组学分析表明，ACLY 阻断通过降低糖酵解和脂肪生成代谢物的水平促进 EC 静止状态。在机制上，ACLY 促进叉头框 O1（FoxO1）和组蛋白 H3 的乙酰化，从而增加 MYC（MYC）的转录，促进促炎和糖脂基因的表达。我们的研究结果表明，ACLY 通过乙酰化介导的 MYC 转录促进 EC 的糖脂生成代谢和促炎反应，提示 ACLY 是治疗败血症相关 EC 功能障碍和器官损伤的潜在治疗靶点。
