Wang Jun-Xian, Zhang Cheng, Fu Lin, Zhang Da-Gang, Wang Bi-Wei, Zhang Zhi-Hui, Chen Yuan-Hua, Lu Yan, Chen Xi, Xu De-Xiang
First Affiliated Hospital, Anhui Medical University, Hefei 230022, China.
Department of Toxicology, Anhui Medical University, Hefei, 230032, China.
Toxicol Lett. 2017 Jan 4;265:38-46. doi: 10.1016/j.toxlet.2016.11.012. Epub 2016 Nov 17.
The peroxisome proliferator-activated receptor gamma (PPAR-γ) 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-γ agonist, on acetaminophen (APAP)-induced acute liver injury. Male CD-1 mice were injected with APAP (300mg/kg). Some mice were pretreated with RSG (20mg/kg) 48, 24 and 1h 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-κB) 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-γ agonists might be effective agents for preventing the progression of APAP-induced acute liver injury.
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，可调节葡萄糖和脂质代谢。本研究的目的是探讨合成的PPAR-γ激动剂罗格列酮（RSG）对乙酰氨基酚（APAP）诱导的急性肝损伤的影响。给雄性CD-1小鼠注射APAP（300mg/kg）。一些小鼠在注射APAP前48、24和1小时用RSG（20mg/kg）进行预处理。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。虽然RSG预处理不影响肝细胞色素P450（CYP）2E1的表达，但它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，并减轻了APAP诱导的急性肝损伤期间肝脏谷胱甘肽的消耗。此外，RSG预处理抑制了APAP诱导的急性肝损伤期间肝核因子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。目前的结果表明，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。
