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Catalase deficiency induces reactive oxygen species mediated pexophagy and cell death in the liver during prolonged fasting
Biofactors ( IF 6 ) Pub Date : 2021-01-26 , DOI: 10.1002/biof.1708
Raghbendra Kumar Dutta 1 , Yunash Maharjan 1 , Joon No Lee 1 , Channy Park 1 , Ye-Shih Ho 2 , Raekil Park 1
Affiliation  

Peroxisomes are dynamic organelles that participate in a diverse array of cellular processes, including β‐oxidation, which produces a considerable amount of reactive oxygen species (ROS). Although we showed that catalase depletion induces ROS‐mediated pexophagy in cells, the effect of catalase deficiency during conditions that favor ROS generation remains elusive in mice. In this study, we reported that prolonged fasting in catalase‐knockout (KO) mice drastically increased ROS production, which induced liver‐specific pexophagy, an autophagic degradation of peroxisomes. In addition, increased ROS generation induced the production of pro‐inflammatory cytokines in the liver tissues of catalase‐KO mice. Furthermore, there was a significant increase in the levels of aspartate transaminase and alanine transaminase as well as apparent cell death in the liver of catalase‐KO mice during prolonged fasting. However, an intra‐peritoneal injection of the antioxidant N‐acetyl‐l‐cysteine (NAC) and autophagy inhibitor chloroquine inhibited the inflammatory response, liver damage, and pexophagy in the liver of catalase‐KO mice during prolonged fasting. Consistently, genetic ablation of autophagy, Atg5 led to suppression of pexophagy during catalase inhibition by 3‐aminotriazole (3AT). Moreover, treatment with chloroquine also ameliorated the inflammatory response and cell death in embryonic fibroblast cells from catalase‐KO mice. Taken together, our data suggest that ROS‐mediated liver‐specific pexophagy observed during prolonged fasting in catalase‐KO mice may be responsible for the process associated with hepatic cell death.

中文翻译:

过氧化氢酶缺乏会在长时间禁食期间诱导活性氧介导的肝脏内自噬和细胞死亡

过氧化物酶体是动态细胞器,参与多种细胞过程,包括产生大量活性氧 (ROS) 的 β-氧化。尽管我们发现过氧化氢酶消耗会诱导细胞中 ROS 介导的外食,但在有利于 ROS 生成的条件下,过氧化氢酶缺乏对小鼠的影响仍然难以捉摸。在这项研究中,我们报道了过氧化氢酶基因敲除 (KO) 小鼠长时间禁食会显着增加 ROS 的产生,从而诱导肝脏特异性外食性吞噬,即过氧化物酶体的自噬降解。此外,增加的 ROS 生成诱导了过氧化氢酶 KO 小鼠肝组织中促炎细胞因子的产生。此外,在长期禁食期间,过氧化氢酶-KO小鼠肝脏中的天冬氨酸转氨酶和丙氨酸转氨酶水平显着增加,并出现明显的细胞死亡。然而,腹膜内注射抗氧化剂 N-乙酰-l-半胱氨酸(NAC)和自噬抑制剂氯喹在长时间禁食期间抑制过氧化氢酶-KO小鼠肝脏的炎症反应、肝损伤和外食。一致地,自噬的遗传消融,Atg5 导致在 3-氨基三唑 (3AT) 过氧化氢酶抑制过程中抑制 pexophagy。此外,氯喹治疗还改善了过氧化氢酶-KO小鼠胚胎成纤维细胞的炎症反应和细胞死亡。综上所述,我们的数据表明,在过氧化氢酶 KO 小鼠长期禁食期间观察到的 ROS 介导的肝脏特异性外食可能是与肝细胞死亡相关的过程的原因。
更新日期:2021-02-10
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