BACKGROUND AIMS Hepatic ischemia-reperfusion (IR) injury is the most common complication that occurs in liver surgery and hemorrhagic shock. ATP citrate lyase (Acly) plays a pivotal role in chromatin modification via generating acetyl-CoA for histone acetylation to influence biological processes. We aim to examine the roles of Acly, which is highly expressed in hepatocytes, in liver IR injury. APPROACH The functions of Acly in hepatic IR injury were examined in the mouse model with hepatocytes-specific knockout of Acly. The Acly target genes were analyzed by CUT&RUN assay and RNA Seq. The relationship between the susceptibility of steatotic liver to IR and Acly was determined by gain of function studies in mice. RESULTS Hepatic deficiency of Acly exacerbated liver IR injury. IR induced Acly nuclear translocation in hepatocytes, which spatially fueled nuclear acetyl-CoA (AcCoA). This alteration was associated with enhanced acetylation of H3K9 and subsequent activation of Foxa2 signaling pathway. Nuclear localization of Acly enabled Foxa2-mediated protective effects after hypoxia-reperfusion (HR) in cultured hepatocytes, while cytosolic Acly demonstrated no effect. The presence of steatosis disrupted Acly nuclear translocation. In steatotic liver, restoration of Acly nuclear localization through over-expression of Rspondin-1 or Rspondin-3 ameliorated the IR-induced injury. CONCLUSION Our results indicate that Acly regulates histone modification via nuclear AcCoA production in hepatic IR. Disruption of Acly nuclear translocation increases the vulnerability of steatotic liver to IR. Nuclear Acly thus may serve as a potential therapeutic target for future interventions in hepatic IR injury, particularly in the context of steatosis.

中文翻译：

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核酸保护肝脏免受缺血再灌注损伤。

背景 目的 肝脏缺血再灌注（IR）损伤是肝脏手术和失血性休克中最常见的并发症。ATP 柠檬酸裂解酶 (Acly) 通过生成乙酰辅酶 A 进行组蛋白乙酰化，从而影响生物过程，从而在染色质修饰中发挥关键作用。我们的目的是研究在肝细胞中高表达的 Acly 在肝脏 IR 损伤中的作用。方法 在肝细胞特异性敲除 Acly 的小鼠模型中检查了 Acly 在肝 IR 损伤中的功能。通过 CUT&RUN 测定和 RNA Seq 分析 Acly 靶基因。通过小鼠功能获得研究确定了脂肪肝对 IR 和 Acly 的易感性之间的关系。结果 Acly 肝缺乏会加剧肝脏 IR 损伤。IR 诱导肝细胞中的 Acly 核易位，从而在空间上促进核乙酰辅酶 A (AcCoA)。这种改变与 H3K9 乙酰化的增强和随后 Foxa2 信号通路的激活有关。Acly 的核定位能够在培养的肝细胞缺氧再灌注 (HR) 后发挥 Foxa2 介导的保护作用，而胞质 Acly 则没有任何作用。脂肪变性的存在破坏了Acly核易位。在脂肪变性肝脏中，通过 Rspondin-1 或 Rspondin-3 的过度表达恢复 Acly 核定位可改善 IR 诱导的损伤。结论 我们的结果表明 Acly 通过肝脏 IR 中核 AcCoA 的产生来调节组蛋白修饰。Acly 核易位的破坏增加了脂肪肝对 IR 的脆弱性。因此，核 Acly 可能作为未来干预肝 IR 损伤的潜在治疗靶点，特别是在脂肪变性的情况下。