Institute of Pharmacology, University of Bern, Inselspital, INO-F, 3010 Bern, Switzerland.
Sunnybrook Health Sciences Centre, University of Toronto, 2075 Bayview Ave, Toronto, ON M4N 3M5, Canada.
Int J Mol Sci. 2021 Mar 23;22(6):3281. doi: 10.3390/ijms22063281.
Acetaminophen (APAP) is one of the most commonly used analgesic and anti-pyretic drugs, and APAP intoxication is one of the main reasons for liver transplantation following liver failure in the Western world. While APAP poisoning ultimately leads to liver necrosis, various programmed cell death modalities have been implicated, including ER stress-triggered apoptosis. The BCL-2 family member BOK (BCL-2-related ovarian killer) has been described to modulate the unfolded protein response and to promote chemical-induced liver injury. We therefore investigated the impact of the loss of BOK following APAP overdosing in mice. Surprisingly, we observed sex-dependent differences in the activation of the unfolded protein response (UPR) in both wildtype (WT) and mice, with increased activation of JNK in females compared with males. Loss of BOK led to a decrease in JNK activation and a reduced percentage of centrilobular necrosis in both sexes after APAP treatment; however, this protection was more pronounced in females. Nevertheless, serum ALT and AST levels of and WT mice were comparable, indicating that there was no major difference in the overall outcome of liver injury. We conclude that after APAP overdosing, loss of BOK affects initiating signaling steps linked to ER stress, but has a more minor impact on the outcome of liver necrosis. Furthermore, we observed sex-dependent differences that might be worthwhile to investigate.
对乙酰氨基酚（APAP）是最常用的镇痛药和退烧药之一，APAP 中毒是西方世界肝衰竭后进行肝移植的主要原因之一。虽然 APAP 中毒最终会导致肝坏死，但各种程序性细胞死亡方式都与肝损伤有关，包括内质网应激触发的细胞凋亡。BCL-2 家族成员 BOK（BCL-2 相关卵巢杀手）已被描述为调节未折叠蛋白反应并促进化学诱导的肝损伤。因此，我们研究了在 APAP 过量的情况下 BOK 缺失对小鼠的影响。令人惊讶的是，我们观察到 WT 和 小鼠中未折叠蛋白反应（UPR）的激活存在性别依赖性差异，与雄性相比，雌性的 JNK 激活增加。APAP 处理后，BOK 缺失导致 JNK 激活减少，双核细胞坏死的比例在两性中降低；然而，这种保护在 雌性中更为明显。尽管如此，和 WT 小鼠的血清 ALT 和 AST 水平相当，表明肝损伤的总体结果没有明显差异。我们得出结论，APAP 过量后，BOK 的缺失会影响与内质网应激相关的起始信号步骤，但对肝坏死的结果影响较小。此外，我们观察到性别依赖性差异，值得进一步研究。
