Protect Effect Of Axin Against Acetaminophen-induced Acute Liver Injury Via Promoting GSH Synthesis

Axin1,a multifunctional scaffold protein,plays a crucial role in cell metabolic homeostasis as it regulates multiple signaling pathways including Wnt,AMPK,mTOR,JNK,P53 pathways,etc.Whole-body deletion of Axinl in mice is lethal,which prevents further study of its physiological role in mammals.As liver is the center for metabolic regulation,we construct an Axinl liver knock-out mice model to investigate its physiological role in the liver.It has been reported that acetaminophen(APAP)leading to liver injury results from the depletion of glutathione by toxic metabolite which directly attacks the hepatic cells.Moreover,it activates a variety of cell responses contributing to APAP-induced hepatotoxicity,partly through activating the c-Jun N-terminal kinase(JNK).In our study,we found that Axinl protects the liver against acetaminophen-induced damage and this effect is associated with glutathione synthesis and JNK pathway.Specifically,Axinl facilitates glutathione synthesis by increasing the level of GSH substrate glutamate and the activity of glutamate cysteine ligase,the rate limiting enzyme for GSH synthesis.When administrating Axinl liver knock-out mice with overdose APAP,GSH deficiency occurs and JNK is activated by increased oxidative stress,which can further amplify cell damage and ultimately result in liver injury and even death in these mice.In all,our finding provides a potential target for development of drugs to prevent and treat APAP-associated toxicities,which is currently still limited.In addition,our research could also be inspiring for further understanding of the physiological and pathophysiological roles of Axinl in metabolic regulation.