| 1 | Liver-specific deletion of mechanistic target of rapamycin does not protect against acetaminophen-induced liver injury in mice显示文摘Background:Acetaminophen(APAP)overdose can cause liver injury and liver failure,which is one of the most common causes of drug-induced liver injury in the United States.Pharmacological activation of autophagy by inhibiting mechanistic target of rapamycin(mTOR)protects against APAP-induced liver injury likely via autophagic removal of APAP-adducts and damaged mitochondria.In the present study,we aimed to investigate the role of genetic ablation of mTOR pathways in mouse liver in APAP-induced liver injury and liver repair/regeneration.Methods:Albumin-Cre(Alb-Cre)mice,mTOR^(f/f) and Raptor^(f/f) mice(C57BL/6J background)were crossbred to produce liver-specific mTOR knockout(L-mTOR KO,Alb Cret/-,mTOR^(f/f))and liver-specific Raptor KO(L-Raptor,Alb Cret/-,Raptor^(f/f))mice.Alb-Cre littermates were used as wild-type(WT)mice.These mice were treated with APAP for various time points for up to 48 h.Liver injury,cell proliferation,autophagy and mTOR activation were determined.Results:We found that genetic deletion of neither Raptor,an important adaptor protein in mTOR complex 1,nor mTOR,in the mouse liver significantly protected against APAP-induced liver injury despite increased hepatic autophagic flux.Genetic deletion of Raptor or mTOR in mouse livers did not affect APAP metabolism and APAP-induced c-Jun N-terminal kinase(JNK)activation,but slightly improved mouse survival likely due to increased hepatocyte proliferation.Conclusions:Our results indicate that genetic ablation of mTOR in mouse livers does not protect against APAP-induced liver injury but may slightly improve liver regeneration and mouse survival after APAP overdose. | Hua Sun Hong-Min Ni Jennifer M.McCracken Jephte Y Akakpo Sam Fulte Tara McKeen Hartmut Jaeschke Hua Wang Wen-Xing Ding | 2021 | Liver Research2021，5，2： | 3 |
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