Hepatic ischaemia/reperfusion (I/R) injury is a major clinical problem during liver surgical procedures, which usually lead to early transplantation failure and higher organ rejection rate, and current effective therapeutic strategies are still limited. Therefore, in‐depth exploring of the molecular mechanisms underlying liver I/R injury is key to the development of new therapeutic methods. β‐arrestins are multifunctional proteins serving as important signalling scaffolds in numerous physiopathological processes, including liver‐specific diseases. However, the role and underlying mechanism of β‐arrestins in hepatic I/R injury remain largely unknown. Here, we showed that only ARRB1, but not ARRB2, was down‐regulated during liver I/R injury. Hepatocyte‐specific overexpression of ARRB1 significantly ameliorated liver damage, as demonstrated by decreases in serum aminotransferases, hepatocellular necrosis and apoptosis, infiltrating inflammatory cells and secretion of pro‐inflammatory cytokines relative to control mice, whereas experiments with ARRB1 knockout mice gotten opposite effects. Mechanistically, ARRB1 directly interacts with ASK1 in hepatocytes and inhibits its TRAF6‐mediated Lysine 6‐linked polyubiquitination, which then prevents the activation of ASK1 and its downstream signalling pathway during hepatic I/R injury. In addition, inhibition of ASK1 remarkably abolished the disruptive effect result from ARRB1 deficiency in liver I/R injury in vivo, indicating that ASK1 was required for ARRB1 function in hepatic I/R injury. In conclusion, we proposed that ARRB1 is a novel protective regulator during liver I/R injury, and modulation of the regulatory axis between ARRB1 and ASK1 could be a novel therapeutic strategy to prevent this pathological process.

中文翻译：

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ARRB1通过拮抗TRAF6介导的赖氨酸6连接的ASK1在肝细胞中的多泛素化，改善了肝脏缺血/再灌注损伤。

肝缺血/再灌注（I / R）损伤是肝脏外科手术过程中的主要临床问题，通常会导致早期移植失败和更高的器官排斥率，并且当前有效的治疗策略仍然有限。因此，深入探索肝脏I / R损伤的分子机制是开发新治疗方法的关键。β-arrestin是多功能蛋白，在包括肝脏特异性疾病在内的许多生理病理过程中，都是重要的信号转导支架。但是，β-arrestins在肝I / R损伤中的作用和潜在机制仍不清楚。在这里，我们显示在肝脏I / R损伤过程中只有ARRB1被降低，而ARRB2没有被下调。肝细胞特异性ARRB1的过度表达可明显改善肝脏损伤，相对于对照小鼠而言，血清转氨酶，肝细胞坏死和凋亡，炎性细胞浸润和促炎性细胞因子的分泌减少所证明，而ARRB1基因敲除小鼠的实验却产生了相反的效果。从机理上讲，ARRB1直接与肝细胞中的ASK1相互作用并抑制其TRAF6介导的赖氨酸6连接的多聚泛素化，从而阻止了肝I / R损伤期间ASK1的激活及其下游信号通路。另外，对ASK1的抑制显着消除了体内ARB1缺乏对肝I / R损伤的破坏作用，表明ASK1是肝I / R损伤中ARRB1功能所必需的。总之，我们提出ARRB1是肝脏I / R损伤期间的新型保护性调节剂，