PDF(Pubmed)
Abstract：
The liver is vulnerable to various hepatotoxins, including carbon tetrachloride (CCl4), which induces oxidative stress and apoptosis by producing reactive oxygen species (ROS) and activating the mitogen-activated protein kinase (MAPK) pathway. Cereblon (CRBN), a multifunctional protein implicated in various cellular processes, functions in the pathogenesis of various diseases; however, its function in liver injury remains unknown. We established a CRBN-knockout (KO) HepG2 cell line and examined its effect on CCl4-induced hepatocellular damage. CRBN-KO cells exhibited reduced sensitivity to CCl4-induced cytotoxicity, as evidenced by decreased levels of apoptosis markers, such as cleaved caspase-3, and aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities. CRBN deficiency enhanced antioxidant defense, with increased superoxide dismutase activity and glutathione ratios (GSH/GSSG), as well as reduced pro-inflammatory cytokine expression. Mechanistically, the protective effects of CRBN deficiency appeared to involve the attenuation of the MAPK-mediated pathways, particularly through decreased phosphorylation of JNK and ERK. Overall, these results suggest the crucial role of CRBN in mediating the hepatocellular response to oxidative stress and inflammation triggered by CCl4 exposure, offering potential clinical implications for liver injury in a wide range of liver diseases.
摘要：
肝脏容易受到各种肝毒素的影响,包括四氯化碳（CCl4），通过产生活性氧（ROS）和激活丝裂原活化蛋白激酶（MAPK）途径诱导氧化应激和凋亡。小脑（CRBN），涉及各种细胞过程的多功能蛋白质，在各种疾病的发病机理中发挥作用；然而，其在肝损伤中的作用尚不清楚。我们建立了CRBN敲除（KO）HepG2细胞系，并检查了其对CCl4诱导的肝细胞损伤的影响。CRBN-KO细胞对CCl4诱导的细胞毒性的敏感性降低，正如凋亡标志物水平降低所证明的那样，例如裂解的caspase-3、天冬氨酸转氨酶(AST)和丙氨酸转氨酶(ALT)活性。CRBN缺乏增强了抗氧化防御，随着超氧化物歧化酶活性和谷胱甘肽比率（GSH/GSSG）的增加，以及减少促炎细胞因子的表达。机械上,CRBN缺乏的保护作用似乎涉及MAPK介导途径的减弱，特别是通过减少JNK和ERK的磷酸化。总的来说,这些结果表明CRBN在介导肝细胞对CCl4暴露引发的氧化应激和炎症反应中的关键作用，为广泛的肝脏疾病中的肝损伤提供潜在的临床意义。
