Catalase deficiency induces reactive oxygen species mediated pexophagy and cell death in the liver during prolonged fasting
Catalase deficiency induces reactive oxygen species mediated pexophagy and cell death in the liver during prolonged fasting
复制标题
DOI：
10.1002/biof.1708
复制
发表时间：
2021-01-26
期刊：
影响因子：
6
通讯作者：
Park, Raekil
中科院分区：
文献类型：
--
作者：
Dutta, Raghbendra Kumar;Maharjan, Yunash;Park, Raekil
过氧体是一种动态细胞器，参与多种细胞过程，包括β-氧化，它产生相当数量的活性氧物种(ROS)。虽然我们发现过氧化氢酶的缺失会导致细胞中ROS介导的吞噬作用，但在有利于ROS产生的条件下，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，我们报道了在过氧化氢酶基因敲除(KO)小鼠中，长时间的禁食显著增加了ROS的产生，从而诱导了肝脏特异性的吞噬，这是一种过氧体的自噬降解。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，在长时间禁食期间，过氧化氢酶-KO小鼠肝脏中天冬氨酸转氨酶和丙氨酸转氨酶的水平以及明显的细胞死亡显著增加。然而，腹腔注射抗氧化剂N-乙酰-L半胱氨酸(NAC)和自噬抑制剂氯喹可抑制长时间禁食期间过氧化氢酶-KO小鼠的炎症反应、肝损伤和肝脏的吞噬作用。在3-氨基三氮唑(3AT)抑制过氧化氢酶的过程中，自噬ATG5的遗传消融导致了自噬的抑制。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介导的肝脏特异性吞噬可能是与肝细胞死亡相关的过程的原因。
Peroxisomes are dynamic organelles that participate in a diverse array of cellular processes, including beta-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.