Induction of Sestrin2 by pterostilbene suppresses ethanol-triggered hepatocyte senescence by degrading CCN1 via p62-dependent selective autophagy
Induction of Sestrin2 by pterostilbene suppresses ethanol-triggered hepatocyte senescence by degrading CCN1 via p62-dependent selective autophagy
复制标题
紫檀芪诱导 Sestrin2 通过 p62 依赖性选择性自噬降解 CCN1，从而抑制乙醇引发的肝细胞衰老
DOI：
10.1007/s10565-021-09635-8
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发表时间：
2021-08-17
影响因子：
6.1
通讯作者：
Lu, Chunfeng
中科院分区：
文献类型：
--
作者：
Jiang, Yiming;Zhou, Ying;Lu, Chunfeng
肝细胞衰老是参与酒精性肝病进展的关键事件。自噬是一个关键的生物过程，通过影响细胞衰老等行为来控制细胞命运。蕨二烯是一种天然化合物，具有保护肝脏的潜力；然而，它对酒精性肝病的影响尚不清楚。本研究旨在探讨蕨二烯对酒精性肝病的治疗作用及其可能机制。我们的结果表明，蕨类化合物能减轻乙醇所致的肝细胞损伤和衰老。有趣的是，蕨类植物降低了乙醇暴露的肝细胞中细胞通讯网络因子1(CCN1)的蛋白丰度，这是实现其抗衰老功能所必需的。体内实验证实了蕨类化合物对酒精中毒小鼠肝细胞的抗衰老作用。刺五加还通过抑制肝脏CCN1的表达，缓解衰老相关的分泌表型(SASP)、氧化还原失衡和脂肪变性。从机制上讲，二苯乙烯苷强迫的CCN1减少依赖于通过自噬机制的转录后调节，而不是转录调节。具体地说，蕨二烯可恢复受损肝细胞的自噬通量，激活p62介导的选择性自噬，识别并引导CCN1进入自溶酶体进行降解。在乙醇处理的肝细胞中，自噬途径的核心上游调节因子Sestrin2(SESN2)的蛋白丰度降低，但可通过与蕨类化合物共同处理而恢复。蕨二烯诱导的SESN2蛋白可挽救乙醇诱导的肝细胞自噬功能障碍，从而减少衰老相关标志物，延缓肝细胞衰老，减轻酒精所致的肝损伤和炎症。综上所述，这项工作发现了一种新的化合物蕨类化合物，具有治疗酒精性肝病的意义，并揭示了其潜在的机制。
Hepatocyte senescence is a key event participating in the progression of alcoholic liver disease. Autophagy is a critical biological process that controls cell fates by affecting cell behaviors like senescence. Pterostilbene is a natural compound with hepatoprotective potential; however, its implication for alcoholic liver disease was not understood. This study was aimed to investigate the therapeutic effect of pterostilbene on alcoholic liver disease and elucidate the potential mechanism. Our results showed that pterostilbene alleviated ethanol-triggered hepatocyte damage and senescence. Intriguingly, pterostilbene decreased the protein abundance of cellular communication network factor 1 (CCN1) in ethanol-exposed hepatocytes, which was essential for pterostilbene to execute its anti-senescent function. In vivo studies verified the anti-senescent effect of pterostilbene on hepatocytes of alcohol-intoxicated mice. Pterostilbene also relieved senescence-associated secretory phenotype (SASP), redox imbalance, and steatosis by suppressing hepatic CCN1 expression. Mechanistically, pterostilbene-forced CCN1 reduction was dependent on posttranscriptional regulation via autophagy machinery but not transcriptional regulation. To be specific, pterostilbene restored autophagic flux in damaged hepatocytes and activated p62-mediated selective autophagy to recognize and lead CCN1 to autolysosomes for degradation. The protein abundance of Sestrin2 (SESN2), a core upstream modulator of autophagy pathway, was decreased in ethanol-administrated hepatocytes but rescued by co-treatment with pterostilbene. Induction of SESN2 protein by pterostilbene rescued ethanol-triggered autophagic dysfunction in hepatocytes, which then reduced senescence-associated markers, postponed hepatocyte senescence, and relieved alcohol-caused liver injury and inflammation. In conclusion, this work discovered a novel compound pterostilbene with therapeutic implications for alcoholic liver disease and uncover its underlying mechanism.Graphical abstract