title: Metformin ameliorates acetaminophen hepatotoxicity via Gadd45β-dependent regulation of JNK signaling in mice.
abstract: OBJECTIVE
  Acetaminophen (APAP) overdose is a leading cause of drug-induced acute liver failure. Prolonged c-Jun N-terminal kinase (JNK) activation plays a central role in APAP-induced liver injury and growth arrest, and DNA damage-inducible 45 beta (Gadd45β) is known to inhibit JNK phosphorylation. Metformin has recently been shown to have hepatoprotective effects. The aim of the present study is to investigate whether metformin mitigates APAP-induced hepatotoxicity and to ascertain the molecular basis of this effect.
  
  
  METHODS
  We used APAP- and/or metformin-treated Gadd45β knockout (KO) mice and wild type (WT) C57BL/6J control mice. Primary mouse hepatocytes were isolated from WT and Gadd45β KO mice were used for in vitro study.
  
  
  RESULTS
  Metformin pretreatment protected against APAP toxicity with decreased liver damage, and inhibited APAP-induced prolonged hepatic JNK phosphorylation in WT mice. Gadd45β expression was increased after APAP treatment, and the expression of Gadd45β was further enhanced by metformin. The effects of metformin on APAP-induced liver injury and JNK phosphorylation were abolished in Gadd45β KO mice. Notably, subtoxic doses of APAP caused cell death and sustained JNK phosphorylation in Gadd45β-deficient primary hepatocytes. In parallel, APAP increased mortality, severe liver injury, and JNK activation in Gadd45β KO mice. Interestingly, metformin administered after APAP treatment protected against APAP-evoked hepatotoxicity in WT mice, but not in Gadd45β KO mice.
  
  
  CONCLUSIONS
  This study is the first to demonstrate that metformin shows protective and therapeutic effects against APAP overdose-evoked hepatotoxicity via Gadd45β-dependent JNK regulation. Metformin would be a promising therapeutic strategy for treatment of APAP overdose.
authors: Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology, University of Science and Technology (UST), Yuseong-gu, Daejeon 305-806, South Korea.
authors: Yong-Hoon
authors: YH
authors: Kim
authors: Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology, University of Science and Technology (UST), Yuseong-gu, Daejeon 305-806, South Korea.
authors: Jung Hwan
authors: JH
authors: Hwang
authors: Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology, University of Science and Technology (UST), Yuseong-gu, Daejeon 305-806, South Korea.
authors: Kyoung-Shim
authors: KS
authors: Kim
authors: Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology, University of Science and Technology (UST), Yuseong-gu, Daejeon 305-806, South Korea.
authors: Jung-Ran
authors: JR
authors: Noh
authors: Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology, University of Science and Technology (UST), Yuseong-gu, Daejeon 305-806, South Korea.
authors: Dong-Hee
authors: DH
authors: Choi
authors: National Creative Research Initiatives Center for Nuclear Receptor Signals and Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju, South Korea.
authors: Don-Kyu
authors: DK
authors: Kim
authors: Korea Research Institute of Standards and Science, Daejeon, South Korea.
authors: Surendar
authors: S
authors: Tadi
authors: Korea Research Institute of Standards and Science, Daejeon, South Korea.
authors: Yong-Hyeon
authors: YH
authors: Yim
authors: National Creative Research Initiatives Center for Nuclear Receptor Signals and Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju, South Korea.
authors: Hueng-Sik
authors: HS
authors: Choi
authors: Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology, University of Science and Technology (UST), Yuseong-gu, Daejeon 305-806, South Korea. Electronic address: chullee@kribb.re.kr.
authors: Chul-Ho
authors: CH
authors: Lee
mesh_terms: D000082:Acetaminophen / Q000633:toxicity; D000818:Animals; D000943:Antigens, Differentiation / Q000378:metabolism*; D056486:Chemical and Drug Induced Liver Injury / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology; D007004:Hypoglycemic Agents / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008297:Male; D008687:Metformin / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015398:Signal Transduction / Q000187:drug effects; D000097642:GADD45 Proteins
chemical_list: D000082:Acetaminophen; D000943:Antigens, Differentiation; D007004:Hypoglycemic Agents; D048031:JNK Mitogen-Activated Protein Kinases; D008687:Metformin; C490125:Gadd45b protein, mouse; D000097642:GADD45 Proteins
keywords: Acetaminophen; Gadd45β; Hepatotoxicity; JNK; Metformin