ZNF281 通过减少 HK2 稳定的 PINK1/Parkin 介导的线粒体自噬来驱动酒精性肝病中的肝细胞衰老,Cell Proliferation

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ZNF281 通过减少 HK2 稳定的 PINK1/Parkin 介导的线粒体自噬来驱动酒精性肝病中的肝细胞衰老
Cell Proliferation ( IF 5.9 ) Pub Date : 2022-12-14 , DOI: 10.1111/cpr.13378
Chunfeng Lu ₁ , Ting Ge ₁ , Yunyun Shao ₁ , Wenqian Cui ₁ , Zhe Li ₁ , Wenxuan Xu ₂ , Xiaofeng Bao ₁

Affiliation

我们研究了一种新分子锌指蛋白 281 (ZNF281) 在乙醇诱导的肝细胞衰老中的作用，并揭示了其潜在机制。进行了实时荧光定量 PCR、蛋白质印迹、免疫荧光染色和酶联免疫吸附试验，以探讨 ZNF281 在肝细胞衰老中的作用。ZNF281 表达在酒精喂养的小鼠肝脏和乙醇处理的肝细胞中均被上调。使用 siRNA 在肝细胞中沉默 ZNF281 可减轻乙醇引起的细胞活力下降和天冬氨酸转氨酶、丙氨酸转氨酶和乳酸脱氢酶释放增加。ZNF281 siRNA 在乙醇暴露下减少了衰老相关的 β-半乳糖苷酶阳性细胞，消除了 G0/G1 期的细胞周期停滞，减少衰老相关的分泌表型和促炎细胞因子（IL-1β 和 IL-6）的释放。在分子水平上，ZNF281 缺陷改变了衰老相关蛋白的表达谱，包括 p53、p21、p16、高迁移率组 AT-hook 1 和磷酸组蛋白 H2A.X 以及端粒酶相关调节因子，包括端粒酶逆转录酶、端粒重复序列结合因子 1 (TRF1) 和 TRF2。ZNF281 敲低促进肝细胞从乙醇诱导的线粒体功能障碍和 ROS 产生中恢复，这与挽救 HK2-PINK1/Parkin 信号介导的线粒体自噬相关。从机制上讲，ZNF281 直接与 HK2 启动子区域内的 5'-GGCGGCGGGCGG-3' 基序结合并转录抑制 HK2 表达。腺相关病毒编码 ZNF281 shRNA 的系统性 ZNF281 敲低保护小鼠免受酒精喂养引起的肝细胞损伤和衰老。这项研究提供了一种新的因子 ZNF281 作为酒精性肝病期间肝细胞衰老的驱动因素。

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ZNF281 drives hepatocyte senescence in alcoholic liver disease by reducing HK2-stabilized PINK1/Parkin-mediated mitophagy

We investigated the role of zinc-finger protein 281 (ZNF281), a novel molecule, in ethanol-induced hepatocyte senescence and uncovered the potential mechanism. Real-time PCR, Western blot, immunofluorescence staining, and enzyme-linked immunosorbent assay were performed to explore the role of ZNF281 in hepatocyte senescence. ZNF281 expression was upregulated in both alcohol-fed mice livers and ethanol-treated hepatocytes. Silence of ZNF281 in hepatocytes using siRNA mitigated ethanol-caused decrease in cell viability and increased release of aspartate aminotransferase, alanine transaminase, and lactate dehydrogenase. ZNF281 siRNA reduced senescence-associated β-galactosidase-positive cells under ethanol exposure, abolished cell cycle arrest at G0/G1 phase, and diminished senescence-associated secretory phenotype and proinflammatory cytokines (IL-1β and IL-6) release. At molecular level, ZNF281 deficiency altered the expression profile of senescence-associated proteins including p53, p21, p16, high mobility group AT-hook 1, and phospho-histone H2A.X and telomerase-associated regulatory factors including telomerase reverse transcriptase, telomeric repeat binding factor 1 (TRF1), and TRF2. ZNF281 knockdown promoted hepatocyte recovery from ethanol-induced mitochondrial dysfunction and ROS production, which was correlated with rescuing HK2-PINK1/Parkin signalling-mediated mitophagy. Mechanistically, ZNF281 directly bound to 5′-GGCGGCGGGCGG-3′ motif within HK2 promoter region and transcriptionally repressed HK2 expression. Systematic ZNF281 knockdown by adeno-associated virus encoding ZNF281 shRNA protected mice from alcohol feeding-caused hepatocyte injury and senescence. This study provides a novel factor ZNF281 as a driver of hepatocyte senescence during alcoholic liver disease.

更新日期：2022-12-14

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