Abstract：
BTB and CNC homology 1 (BACH1) regulates biological processes, including energy metabolism and oxidative stress. Insufficient liver regeneration after hepatectomy remains an issue for surgeons. The Pringle maneuver is widely used during hepatectomy and induces ischemia/reperfusion (I/R) injury in hepatocytes. A rat model of two-thirds partial hepatectomy with repeated I/R treatment was used to simulate clinical hepatectomy with Pringle maneuver. Delayed recovery of liver function after hepatectomy with the repeated Pringle maneuver in clinic and impaired liver regeneration in rat model were observed. Highly elevated lactate levels, along with reduced mitochondrial complex III and IV activities in liver tissues, indicated that the glycolytic phenotype was promoted after hepatectomy with repeated I/R. mRNA expression profile analysis of glycolysis-related genes in clinical samples and further verification experiments in rat models showed that high BACH1 expression levels correlated with the glycolytic phenotype after hepatectomy with repeated I/R. BACH1 overexpression restricted the proliferative potential of hepatocytes stimulated with HGF. High PDK1 expression and high lactate levels, together with low mitochondrial complex III and IV activities and reduced ATP concentrations, were detected in BACH1-overexpressing hepatocytes with HGF stimulation. Moreover, HO-1 expression was downregulated, and oxidative stress was exacerbated in the BACH1-overexpressing hepatocytes with HGF stimulation. Cell experiments involving repeated hypoxia/reoxygenation revealed that reactive oxygen species accumulation triggered the TGF-β1/BACH1 axis in hepatocytes. Finally, inhibiting BACH1 with the inhibitor hemin effectively restored the liver regenerative ability after hepatectomy with repeated I/R. These results provide a potential therapeutic strategy for impaired liver regeneration after repeated I/R injury.
摘要：
BTB和CNC同源性1（BACH1）调节生物过程，包括能量代谢和氧化应激。肝切除术后肝再生不足仍然是外科医生的问题。Pringle操作在肝切除术中广泛使用，并引起肝细胞的缺血/再灌注（I/R）损伤。使用重复I/R治疗的三分之二部分肝切除术的大鼠模型来模拟Pringle动作的临床肝切除术。观察到临床反复Pringle操作肝切除术后肝功能恢复延迟和大鼠模型肝再生受损。乳酸水平高度升高，随着肝脏组织中线粒体复合物III和IV活性的降低，提示反复I/R肝切除术后糖酵解表型得到促进临床样本中糖酵解相关基因的mRNA表达谱分析和大鼠模型的进一步验证实验表明，反复I/R肝切除术后BACH1的高表达水平与糖酵解表型相关。BACH1过表达限制了HGF刺激的肝细胞的增殖潜力。高PDK1表达和高乳酸水平，线粒体复合物III和IV活性低，ATP浓度降低，用HGF刺激在BACH1过表达的肝细胞中检测到。此外，HO-1表达下调，在HGF刺激下，BACH1过表达的肝细胞中的氧化应激加剧。涉及反复缺氧/复氧的细胞实验表明，活性氧的积累触发了肝细胞中的TGF-β1/BACH1轴。最后,抑制剂血红素抑制BACH1可有效恢复反复I/R肝切除术后的肝脏再生能力。这些结果为反复I/R损伤后受损的肝再生提供了潜在的治疗策略。
