FK866 attenuates acute hepatic failure through c-jun-N-terminal kinase (JNK)-dependent autophagy

FK866 attenuates acute hepatic failure through c-jun-N-terminal kinase (JNK)-dependent autophagy

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Abstract 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 here 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 read more 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.