Oroxylin a promotes PGC-1α/Mfn2 signaling to attenuate hepatocyte pyroptosis via blocking mitochondrial ROS in alcoholic liver disease
Oroxylin a promotes PGC-1α/Mfn2 signaling to attenuate hepatocyte pyroptosis via blocking mitochondrial ROS in alcoholic liver disease
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DOI：
10.1016/j.freeradbiomed.2020.03.031
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发表时间：
2020-06-01
影响因子：
7.4
通讯作者：
Zheng, Shizhong
中科院分区：
文献类型：
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作者：
Kai, Jun;Yang, Xiang;Zheng, Shizhong
背景资料：酒精性肝病（alcoholic liver disease，ALD）是一种以肝细胞脂质异常沉积和过度氧化应激为特征的疾病。近年来，ALD中发现了一种新的细胞程序性死亡（programmedcelldeath，简称Pyroptosis），这为ALD的治疗提供了新的思路。方法：雄性ICR小鼠分别给予Lieber-De-Carli饲料（Dyets）和等热量流质饲料8周，同时采用酒精中毒模型。取血和肝以评价木脂素A的功效。结果：我们的研究发现，木脂素A通过NLRP 3炎性体依赖的经典caspase-1途径抑制肝细胞凋亡。结果表明，木脂素A通过减少ROS积累来抑制NLRP 3炎性小体活化。此外，oroxylin A上调mitofusin 2（Mfn 2），以抵抗脂质沉积和细胞衍生的ROS过度产生。过氧化物酶体增殖物激活受体γ辅激活因子1 α（Peroxisome Proliferator-Activated Receptor gamma Coactivator 1 alpha，PGC-1 alpha）作为Mfn 2的上游介导因子，能促进Mfn 2的转录。
Background: It is well acknowledged that alcoholic liver disease (ALD) is widely prevalent all over the world, characterized by aberrant lipid deposition and excessive oxidative stress in hepatocytes. Recently, pyroptosis, a new type of programmed cell death, has been found in ALD, which provides new ideas for the treatment of ALD.Methods: Male ICR mice were treated with the Lieber-De-Carli diet (Dyets) or isocaloric liquid diet for 8 weeks, and binge alcohol model was also used for ALD. Blood and livers were taken to evaluate the efficacy of oroxylin A. The levels of factors related to hepatocyte pyroptosis were measured via western blot analyses, immuno-fluorescence analyses and quantitative reverse transcriptase in vitro.Result: Our study found that oroxylin A suppressed hepatocyte pyroptosis through a NLRP3 inflammasome dependent-canonical caspase-1 pathway. Results illuminated that oroxylin A inhibited NLRP3 inflammasome activation by reducing ROS accumulation. Furthermore, oroxylin A upregulated mitofusin 2 (Mfn2) to resist lipid deposition and mitochondria-derived ROS overproduction. As an upstream mediator of Mfn2, peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1 alpha), a major regulator of mitochondria, was found to promote transcription of Mfn2 under oroxylin A treatment.Conclusion: Our research revealed that oroxylin A could alleviate ALD via PGC-1 alpha/Mfn2 signaling mediated canonical pyroptosis pathway resistance.