Protective effect of rosiglitazone against acetaminophen-induced acute liver injury is associated with down-regulation of hepatic NADPH oxidases
Protective effect of rosiglitazone against acetaminophen-induced acute liver injury is associated with down-regulation of hepatic NADPH oxidases
复制标题
罗格列酮对对乙酰氨基酚诱导的急性肝损伤的保护作用与肝脏 NADPH 氧化酶的下调有关
DOI：
10.1016/j.toxlet.2016.11.012
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发表时间：
2017-01-04
影响因子：
3.5
通讯作者：
Xu, De-Xiang
中科院分区：
文献类型：
--
作者：
Wang, Jun-Xian;Zhang, Cheng;Xu, De-Xiang
过氧化物酶体增殖物激活受体γ（PPAR - γ）是一种配体激活的核受体，可调节糖和脂质代谢。本研究的目的是探讨罗格列酮（RSG），一种合成的PPAR - γ激动剂，对乙酰氨基酚（APAP）诱导的急性肝损伤的影响。雄性CD - 1小鼠注射APAP（300 mg/kg）。一些小鼠在APAP注射前48、24和1小时用RSG（20 mg/kg）预处理。正如预期的那样，RSG预处理减轻了APAP诱导的急性肝损伤。此外，RSG预处理减轻了APAP诱导的肝细胞死亡并提高了存活率。尽管它不影响肝细胞色素P450（CYP）2E1的表达，但RSG预处理减轻了肝谷胱甘肽过氧化物酶（GSH - Px）、谷胱甘肽还原酶（GSH - Rd）和谷胱甘肽S - 转移酶（GST）活性的降低，抑制了肝烟酰胺腺嘌呤二核苷酸磷酸（NADPH）氧化酶（NOX）- 2和NOX - 4的上调，并缓解了APAP诱导的急性肝损伤过程中肝GSH的耗竭。此外，RSG预处理抑制了APAP诱导的急性肝损伤过程中肝核因子κB（NF - κB）和细胞外信号相关激酶（ERK）/丝裂原活化蛋白激酶（MAPK）信号通路的激活。这些结果为RSG介导的对APAP诱导的急性肝损伤的保护作用提供了一种新的机制解释。本研究结果表明，合成的PPAR - γ激动剂可能是预防APAP诱导的急性肝损伤进展的有效药物。（C）2016爱思唯尔爱尔兰有限公司。保留所有权利。
The peroxisome proliferator-activated receptor gamma (PPAR-gamma) is a ligand-activated nuclear receptor that regulates glucose and lipid metabolism. The aim of the present study was to investigate the effects of rosiglitazone (RSG), a synthetic PPAR-gamma agonist, on acetaminophen (APAP)-induced acute liver injury. Male CD-1 mice were injected with APAP (300 mg/kg). Some mice were pretreated with RSG (20 mg/kg) 48, 24 and 1 h before APAP injection. As expected, RSG pretreatment alleviated APAP-induced acute liver injury. Moreover, RSG pretreatment attenuated APAP-induced hepatic cell death and improved the survival. Although it did not affect hepatic cytochrome P450 (CYP) 2E1 expression, RSG pretreatment attenuated reduction of hepatic glutathione peroxidase (GSH-Px), glutathione reductase (GSH-Rd) and glutathione S-transferase (GST) activities, inhibited upregulation of hepatic nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX)-2 and NOX-4, and alleviated hepatic GSH depletion during APAP-induced acute liver injury. In addition, RSG pretreatment suppressed activation of hepatic nuclear factor kappa B (NF-kappa B) and extracellular signal-related kinase (ERK)/mitogen-activated protein kinase (MAPK) signaling during APAP-induced acute liver injury. These results provide a novel mechanistic explanation for RSG-mediated protection against APAP-induced acute liver injury. The present results suggest that synthetic PPAR-gamma agonists might be effective agents for preventing the progression of APAP-induced acute liver injury. (C) 2016 Elsevier Ireland Ltd. All rights reserved.