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Liver-specific deletion of mechanistic target of rapamycin does not protect against acetaminophen-induced liver injury in mice

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Liver Research 2021年第2期5卷 79-87页

作者： Hua Sun Hong-Min Ni Jennifer M.McCracken Jephte Y Akakpo sam fulte Tara McKeen Hartmut Jaeschke Hua Wang Wen-Xing Ding Department of Pharmacology Toxicology and TherapeuticsThe University of Kansas Medical CenterKansas CityKSUSA Department of Oncology The First Affiliated Hospital of Anhui Medical UniversityHefeiChina

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.

关键词： Acetaminophen(APAP) Autophagy Hepatotoxicity Liver injury Liver regeneration Mechanistic target of rapamycin(mTOR) Regulatory associated protein of mTOR complex(Raptor)

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