Apolipoprotein A-1 protected hepatic ischaemia-reperfusion injury through suppressing macrophage pyroptosis via TLR4-NF-κB pathway
Apolipoprotein A-1 protected hepatic ischaemia-reperfusion injury through suppressing macrophage pyroptosis via TLR4-NF-κB pathway
复制标题
载脂蛋白A - 1通过Toll样受体4（TLR4）-核因子κB（NF - κB）通路抑制巨噬细胞焦亡，从而减轻肝脏缺血 - 再灌注损伤 。
DOI：
10.1111/liv.15448
复制
发表时间：
2022-10-24
影响因子：
6.7
通讯作者：
Li, Chang-Xian
中科院分区：
文献类型：
--
作者：
Chen, Rui-Xiang;Jiang, Wang-Jie;Li, Chang-Xian
背景与目的：载脂蛋白A-1 （ApoA-1）是高密度脂蛋白的主要载脂蛋白，在心血管疾病中起抗动脉粥样硬化作用，在各种炎症和感染性疾病中发挥抗炎作用。然而，ApoA-1在肝缺血-再灌注（I/R）损伤中的作用和机制尚不清楚。方法：在本研究中，我们检测了人肝移植后ApoA-1的表达。采用ApoA-1敲除小鼠、ApoA-1模拟肽D-4F处理小鼠及相应对照小鼠制作小鼠肝脏部分I/R损伤模型，观察ApoA-1对肝脏损伤、炎症反应及细胞死亡的影响。分离原代肝细胞和巨噬细胞进行体外研究。结果：人肝移植后及肝I/R损伤小鼠肝脏中ApoA-1表达下调。ApoA-1缺乏加重了肝I/R损伤引起的肝损伤和炎症反应。有趣的是，我们发现在肝I/R损伤的急性期，ApoA-1缺乏增加了焦亡而不是凋亡，主要发生在巨噬细胞而不是肝细胞中。对焦亡的抑制弥补了ApoA-1缺乏的不利影响。此外，证实了ApoA-1通过TLR4- nf -kappa B途径介导了焦亡过程的上调，TLR4抑制显著改善了肝I/R损伤。此外，我们证实D-4F可改善肝I/R损伤。结论：我们的研究发现ApoA-1通过TLR4-NF-kappa B途径抑制巨噬细胞焦亡，对肝脏I/R损伤具有保护作用。ApoA-1的作用可能为肝I/R损伤的治疗提供新的途径。
Background and Aims: Apolipoprotein A-1 (ApoA-1), the major apolipoprotein of high-density lipoprotein, plays anti-atherogenic role in cardiovascular diseases and exerts anti-inflammation effect in various inflammatory and infectious diseases. However, the role and mechanism of ApoA-1 in hepatic ischaemia-reperfusion (I/R) injury is unknown.Methods: In this study, we measured ApoA-1 expression in human liver grafts after transplantation. Mice partial hepatic I/R injury model was made in ApoA-1 knockout mice, ApoA-1 mimetic peptide D-4F treatment mice and corresponding control mice to examine the effect of ApoA-1 on liver damage, inflammation response and cell death. Primary hepatocytes and macrophages were isolated for in vitro study.Results: The results showed that ApoA-1 expression was down-regulated in human liver grafts after transplantation and mice livers subjected to hepatic I/R injury. ApoA-1 deficiency aggravated liver damage and inflammation response induced by hepatic I/R injury. Interestingly, we found that ApoA-1 deficiency increased pyroptosis instead of apoptosis during acute phase of hepatic I/R injury, which mainly occurred in macrophages rather than hepatocytes. The inhibition of pyroptosis compensated for the adverse impact of ApoA-1 deficiency. Furthermore, the up-regulated pyroptosis process was testified to be mediated by ApoA-1 through TLR4-NF-kappa B pathway and TLR4 inhibition significantly improved hepatic I/R injury. In addition, we confirmed that D-4F ameliorated hepatic I/R injury.Conclusions: Our study has identified the protective role of ApoA-1 in hepatic I/R injury through inhibiting pyroptosis in macrophages via TLR4-NF-kappa B pathway. The effect of ApoA-1 may provide a novel therapeutic approach for hepatic I/R injury.