Yong-Hoon Kim1, Jung Hwan Hwang1, Kyoung-Shim Kim1, Jung-Ran Noh1, Dong-Hee Choi1, Don-Kyu Kim2, Surendar Tadi3, Yong-Hyeon Yim3, Hueng-Sik Choi2, Chul-Ho Lee4. 1. Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology, University of Science and Technology (UST), Yuseong-gu, Daejeon 305-806, South Korea. 2. 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. 3. Korea Research Institute of Standards and Science, Daejeon, South Korea. 4. 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.
Abstract
BACKGROUND & AIMS: 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.
BACKGROUND & AIMS: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 APAPtoxicity 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 APAPoverdose-evoked hepatotoxicity via Gadd45β-dependent JNK regulation. Metformin would be a promising therapeutic strategy for treatment of APAPoverdose.
Authors: Nicola Veronese; Cyrus Cooper; Jean-Yves Reginster; Marc Hochberg; Jaime Branco; Olivier Bruyère; Roland Chapurlat; Nasser Al-Daghri; Elaine Dennison; Gabriel Herrero-Beaumont; Jean-François Kaux; Emmanuel Maheu; René Rizzoli; Roland Roth; Lucio C Rovati; Daniel Uebelhart; Mila Vlaskovska; André Scheen Journal: Semin Arthritis Rheum Date: 2019-01-11 Impact factor: 5.532
Authors: K Kalinsky; T Zheng; H Hibshoosh; X Du; P Mundi; J Yang; S Refice; S M Feldman; B Taback; E Connolly; K D Crew; M A Maurer; D L Hershman Journal: Clin Transl Oncol Date: 2016-06-15 Impact factor: 3.405