Nuclear acly protects liver from ischemia-reperfusion injury

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.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.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.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.