Graduate School, Southern Medical University, 1023 Shatai Nan Road, Guangzhou, 510515, China.
Department of Infectious Diseases, Wuhan General Hospital, 627 Wuluo Road, Wuhan, 430070, China.
Sci Rep. 2017 May 19;7(1):2206. doi: 10.1038/s41598-017-02318-7.
FK866 exhibits a protective effect on D-galactosamine (GaIN)/lipopolysaccharide (LPS) and concanavalin A (ConA)-induced acute liver failure (ALF), but the mechanism by which FK866 affords this benefit has not yet been elucidated. Autophagy has a protective effect on acute liver injury. However, the contribution of autophagy to FK866-conferred hepatoprotection is still unclear. This study aimed to investigate whether FK866 could attenuate GaIN/LPS and ConA-induced ALF through c-jun-N-terminal kinase (JNK)-dependent autophagy. In vivo, Mice were pretreated with FK866 at 24, 12, and 0.5 h before treatment with GaIN/LPS and ConA. 3-methyladenine (3MA) or rapamycin were used to determine the role of autophagy in FK866-conferred hepatoprotection. In primary hepatocytes, autophagy was inhibited by 3MA or autophagy-related protein 7 (Atg7) small interfering RNA (siRNA). JNK was suppressed by SP600125 or Jnk siRNA. FK866 alleviated hepatotoxicity and increased autophagy while decreased JNK activation. Suppression of autophagy abolished the FK866-conferred protection. Inhibition of JNK increased autophagy and exhibited strongly protective effect. Collectively, FK866 could ameliorate GaIN/LPS and ConA-induced ALF through induction of autophagy while suppression of JNK. These findings suggest that FK866 acts as a simple and applicable preconditioning intervention to protect against ALF; autophagy and JNK may also provide therapeutic targets for ALF treatment.
FK866 对 D-半乳糖胺（GaIN）/脂多糖（LPS）和伴刀豆球蛋白 A（ConA）诱导的急性肝衰竭（ALF）具有保护作用，但 FK866 发挥这种益处的机制尚未阐明。自噬对急性肝损伤具有保护作用。然而，自噬对 FK866 介导的肝保护作用的贡献尚不清楚。本研究旨在探讨 FK866 是否可以通过 c-jun-N-末端激酶（JNK）依赖性自噬来减轻 GaIN/LPS 和 ConA 诱导的 ALF。在体内，在给予 GaIN/LPS 和 ConA 之前，24、12 和 0.5 h 用 FK866 预处理小鼠。用 3-甲基腺嘌呤（3MA）或雷帕霉素来确定自噬在 FK866 介导的肝保护中的作用。在原代肝细胞中，用 3MA 或自噬相关蛋白 7（Atg7）小干扰 RNA（siRNA）抑制自噬。用 SP600125 或 Jnk siRNA 抑制 JNK。FK866 减轻肝毒性，增加自噬，同时降低 JNK 激活。自噬的抑制消除了 FK866 介导的保护作用。JNK 的抑制增加了自噬，并表现出强烈的保护作用。总之，FK866 通过诱导自噬减轻 GaIN/LPS 和 ConA 诱导的 ALF，同时抑制 JNK。这些发现表明 FK866 作为一种简单且适用的预处理干预措施，可以预防 ALF；自噬和 JNK 也可能为 ALF 的治疗提供治疗靶点。
