The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines and The SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
Center for Drug Safety Evaluation and Research, Innovation Research Institute of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
Cell Biol Toxicol. 2023 Dec;39(6):2685-2707. doi: 10.1007/s10565-023-09795-9. Epub 2023 Feb 21.
Improper use of acetaminophen (APAP) will induce acute liver failure. This study is designed to investigate whether early growth response-1 (EGR1) participated in the promotion on liver repair and regeneration after APAP-induced hepatotoxicity provided by natural compound chlorogenic acid (CGA). APAP induced the nuclear accumulation of EGR1 in hepatocytes regulated by extracellular-regulated protein kinase (ERK)1/2. In Egr1 knockout (KO) mice, the liver damage caused by APAP (300 mg/kg) was more severe than in wild-type (WT) mice. Results of chromatin immunoprecipitation and sequencing (ChIP-Seq) manifested that EGR1 could bind to the promoter region in Becn1, Ccnd1, and Sqstm1 (p62) or the catalytic/modify subunit of glutamate-cysteine ligase (Gclc/Gclm). Autophagy formation and APAP-cysteine adduct (APAP-CYS) clearance were decreased in Egr1 KO mice administered with APAP. The EGR1 deletion reduced hepatic cyclin D1 expression at 6, 12, or 18 h post APAP administration. Meanwhile, the EGR1 deletion also decreased hepatic p62, Gclc and Gclm expression, GCL enzymatic activity, and glutathione (GSH) content and decreased nuclear factor erythroid 2-related factor 2 (Nrf2) activation and thus aggravated oxidative liver injury induced by APAP. CGA increased EGR1 nuclear accumulation; enhanced hepatic Ccnd1, p62, Gclc, and Gclm expression; and accelerated the liver regeneration and repair in APAP-intoxicated mice. In conclusion, EGR1 deficiency aggravated liver injury and obviously delayed liver regeneration post APAP-induced hepatotoxicity through inhibiting autophagy, enhancing liver oxidative injury, and retarding cell cycle progression, but CGA promoted the liver regeneration and repair in APAP-intoxicated mice via inducing EGR1 transcriptional activation.
对乙酰氨基酚（APAP）使用不当会导致急性肝衰竭。本研究旨在探讨天然化合物绿原酸（CGA）是否通过早期生长反应-1（EGR1）参与 APAP 诱导的肝毒性后肝脏修复和再生的促进作用。APAP 诱导细胞外调节蛋白激酶（ERK）1/2 调节的肝细胞中 EGR1 的核积累。在 Egr1 敲除（KO）小鼠中，APAP（300mg/kg）引起的肝损伤比野生型（WT）小鼠更严重。染色质免疫沉淀和测序（ChIP-Seq）的结果表明，EGR1 可以与 Becn1、Ccnd1 和 Sqstm1（p62）或谷氨酸半胱氨酸连接酶的催化/修饰亚基（Gclc/Gclm）的启动子区域结合。给予 APAP 的 Egr1 KO 小鼠中自噬形成和 APAP-半胱氨酸加合物（APAP-CYS）清除减少。EGR1 缺失降低了 APAP 给药后 6、12 或 18 小时的肝周期蛋白 D1 表达。同时，EGR1 缺失还降低了肝 p62、Gclc 和 Gclm 表达、GCL 酶活性和谷胱甘肽（GSH）含量，降低了核因子红细胞 2 相关因子 2（Nrf2）的激活，从而加重了 APAP 诱导的氧化肝损伤。CGA 增加了 EGR1 的核积累；增强了肝 Ccnd1、p62、Gclc 和 Gclm 的表达；并加速了 APAP 中毒小鼠的肝再生和修复。总之，EGR1 缺乏通过抑制自噬、增强肝氧化损伤和延迟细胞周期进程，加重 APAP 诱导的肝损伤，明显延迟肝再生，但 CGA 通过诱导 EGR1 转录激活促进 APAP 中毒小鼠的肝再生和修复。
