Ischemic preconditioning attenuates ischemia/reperfusion injury in rat steatotic liver: role of heme oxygenase-1-mediated autophagy.
Ischemic preconditioning attenuates ischemia/reperfusion injury in rat steatotic liver: role of heme oxygenase-1-mediated autophagy.
复制标题
缺血预处理减轻大鼠脂肪肝缺血/再灌注损伤：血红素加氧酶 1 介导的自噬的作用
DOI：
10.18632/oncotarget.13281
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发表时间：
2016-11-29
期刊：
影响因子：
--
通讯作者：
Ouyang M
中科院分区：
文献类型：
--
作者：
Liu A;Guo E;Yang J;Li R;Yang Y;Liu S;Hu J;Jiang X;Dirsch O;Dahmen U;Sun J;Ouyang M
脂肪肝更容易受到缺血/再灌注（I/R）损伤，缺血预处理（IPC）可以改善这种损伤。自噬对肝缺血再灌注损伤和脂肪肝衰退具有保护作用。本研究的目的是检验以下假设：脂肪肝对 I/R 损伤的易感性增加与肝自噬缺陷相关，而 IPC 可以通过血红素加氧酶-1 (HO-1) 信号传导来恢复肝自噬缺陷。高脂肪饮食诱发肥胖和肝脂肪变性。肥胖会损害肝脏自噬活性并降低肝脏 HO-1 表达。 HO-1 的诱导恢复了自噬活性并抑制了钙蛋白酶 2 活性。此外，抑制钙蛋白酶 2 活性也能恢复自噬活性。与瘦肝脏相比，脂肪变性肝脏对 I/R 损伤的反应中线粒体功能障碍和肝细胞损伤显着增加。这种对 I/R 损伤敏感性的增加与脂肪肝中肝自噬活性缺陷有关。 IPC 增加 I/R 损伤后脂肪肝中的自噬并减少线粒体功能障碍和肝细胞损伤。此外，IPC 增加了 HO-1 的表达。抑制 HO-1 会降低 IPC 诱导的自噬，增加钙蛋白酶 2 活性，并减弱 IPC 对 I/R 损伤的保护作用。抑制钙蛋白酶 2 可恢复缺血再灌注后脂肪肝中的自噬缺陷并减轻线粒体功能障碍。总的来说，IPC 可能会通过 HO-1 介导的自噬改善脂肪肝损伤并恢复线粒体功能。
Steatotic livers are more susceptible to ischemia/reperfusion (I/R) injury, which is ameliorated by ischemic preconditioning (IPC). Autophagy possesses protective action on liver I/R injury and declines in steatotic livers. The aim of this study was to test the hypothesis that the increased susceptibility of steatotic livers to I/R injury was associated with defective hepatic autophagy, which could be restored by IPC via heme oxygenase-1 (HO-1) signaling. Obesity and hepatic steatosis was induced using a high fat diet. Obesity impaired hepatic autophagy activity and decreased hepatic HO-1 expression. Induction of HO-1 restored autophagy activity and inhibited calpain 2 activity. Additionally, suppression of calpain 2 activity also restored autophagy activity. Mitochondrial dysfunction and hepatocellular injury were significantly increased in steatotic livers compared to lean livers in response to I/R injury. This increase in sensitivity to I/R injury was associated with defective hepatic autophagy activity in steatotic livers. IPC increased autophagy and reduced mitochondrial dysfunction and hepatocellular damage in steatotic livers following I/R injury. Furthermore, IPC increased HO-1 expression. Inhibition of HO-1 decreased the IPC-induced autophagy, increased calpain 2 activity and diminished the protective effect of IPC against I/R injury. Inhibition of calpain 2 restored autophagic defect and attenuated mitochondrial dysfunction in steatotic livers after I/R. Collectively, IPC might ameliorate steatotic liver damage and restore mitochondrial function via HO-1-mediated autophagy.