PMID- 34504721
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20221214
IS  - 2096-2878 (Print)
IS  - 2542-5684 (Electronic)
VI  - 5
IP  - 2
DP  - 2021 Jun
TI  - Liver-specific deletion of mechanistic target of rapamycin does not protect 
      against acetaminophen-induced liver injury in mice.
PG  - 79-87
LID - 10.1016/j.livres.2021.03.001 [doi]
AB  - 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 Cre+/-, mTOR(f/f)) and liver-specific Raptor KO 
      (L-Raptor, Alb Cre+/-, 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.
FAU - Sun, Hua
AU  - Sun H
AD  - Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas 
      Medical Center, Kansas City, KS, USA.
AD  - Department of Oncology, The First Affiliated Hospital of Anhui Medical 
      University, Hefei, China.
FAU - Ni, Hong-Min
AU  - Ni HM
AD  - Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas 
      Medical Center, Kansas City, KS, USA.
FAU - McCracken, Jennifer M
AU  - McCracken JM
AD  - Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas 
      Medical Center, Kansas City, KS, USA.
FAU - Akakpo, Jephte Y
AU  - Akakpo JY
AD  - Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas 
      Medical Center, Kansas City, KS, USA.
FAU - Fulte, Sam
AU  - Fulte S
AD  - Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas 
      Medical Center, Kansas City, KS, USA.
FAU - McKeen, Tara
AU  - McKeen T
AD  - Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas 
      Medical Center, Kansas City, KS, USA.
FAU - Jaeschke, Hartmut
AU  - Jaeschke H
AD  - Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas 
      Medical Center, Kansas City, KS, USA.
FAU - Wang, Hua
AU  - Wang H
AD  - Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas 
      Medical Center, Kansas City, KS, USA.
AD  - Department of Oncology, The First Affiliated Hospital of Anhui Medical 
      University, Hefei, China.
FAU - Ding, Wen-Xing
AU  - Ding WX
AD  - Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas 
      Medical Center, Kansas City, KS, USA.
LA  - eng
GR  - P30 GM118247/GM/NIGMS NIH HHS/United States
GR  - R01 DK102142/DK/NIDDK NIH HHS/United States
PT  - Journal Article
DEP - 20210319
PL  - China
TA  - Liver Res
JT  - Liver research
JID - 101705555
PMC - PMC8425470
MID - NIHMS1732651
OTO - NOTNLM
OT  - Acetaminophen (APAP)
OT  - Autophagy
OT  - Hepatotoxicity
OT  - Liver injury
OT  - Liver regeneration
OT  - Mechanistic target of rapamycin (mTOR)
OT  - Regulatory associated protein of mTOR complex (Raptor)
COIS- Declaration of competing interest The authors declare that they have no conflict 
      of interest.
EDAT- 2021/09/11 06:00
MHDA- 2021/09/11 06:01
PMCR- 2021/09/08
CRDT- 2021/09/10 07:01
PHST- 2021/09/10 07:01 [entrez]
PHST- 2021/09/11 06:00 [pubmed]
PHST- 2021/09/11 06:01 [medline]
PHST- 2021/09/08 00:00 [pmc-release]
AID - 10.1016/j.livres.2021.03.001 [doi]
PST - ppublish
SO  - Liver Res. 2021 Jun;5(2):79-87. doi: 10.1016/j.livres.2021.03.001. Epub 2021 Mar 
      19.