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Arch Toxicol. 2018 Aug;92(8):2563-2572. doi: 10.1007/s00204-018-2247-3. Epub 2018 Jun 25.

Hepatocyte SHP deficiency protects mice from acetaminophen-evoked liver injury in a JNK-signaling regulation and GADD45β-dependent manner.

Kim YH1,2, Noh JR3, Hwang JH3,4, Kim KS3,4, Choi DH3, Kim JH3, Moon SJ3,4, Choi JH3,4, Hérault Y5,6,7,8,9, Lee TG10, Choi HS11, Lee CH12,13.

Author information

1
Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology, 125 Gwahak-ro, Yuseong-gu, Daejeon, 34141, South Korea. yhoonkim@kribb.re.kr.
2
University of Science and Technology (UST), Daejeon, 34113, South Korea. yhoonkim@kribb.re.kr.
3
Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology, 125 Gwahak-ro, Yuseong-gu, Daejeon, 34141, South Korea.
4
University of Science and Technology (UST), Daejeon, 34113, South Korea.
5
Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, 1 rue Laurent Fries, 67404, Illkirch, France.
6
Centre National de la Recherche Scientifique, UMR7104, Illkirch, France.
7
Institut National de la Santé et de la Recherche Médicale, U1258, Illkirch, France.
8
Université de Strasbourg, Illkirch, France.
9
CELPHEDIA, PHENOMIN, Institut Clinique de la Souris, ICS, 1 rue Laurent Fries, 67404, Illkirch, France.
10
Center for Nano-Bio Measurement, Korea Research Institute of Standard and Science, 267 Gajeong-ro, Yuseong-gu, Daejeon, 34113, South Korea.
11
National Creative Research Initiatives Center for Nuclear Receptor Signals and Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju, 61186, South Korea.
12
Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology, 125 Gwahak-ro, Yuseong-gu, Daejeon, 34141, South Korea. chullee@kribb.re.kr.
13
University of Science and Technology (UST), Daejeon, 34113, South Korea. chullee@kribb.re.kr.

Abstract

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; however, growth arrest and DNA damage-inducible 45 beta (GADD45β) is known to inhibit JNK phosphorylation. The orphan nuclear receptor small heterodimer partner (SHP, NR0B2) acts as a transcriptional co-repressor of various genes. The aim of the present study was to investigate the role of SHP in APAP-evoked hepatotoxicity. We used lethal (750 mg/kg) or sublethal (300 mg/kg) doses of APAP-treated wild-type (WT), Shp knockout (Shp-/-), hepatocyte-specific Shp knockout (Shphep-/-), and Shp and Gadd45β double knockout (Shp-/-Gadd45β-/-) mice for in vivo studies. Primary mouse hepatocytes were used for a comparative in vitro study. SHP deficiency protected against APAP toxicity with an increased survival rate, decreased liver damage, and inhibition of prolonged hepatic JNK phosphorylation in mice, which was independent of APAP metabolism regulation. Furthermore, Shphep-/- mice showed diminished APAP hepatotoxicity compared with WT mice. SHP-deficient primary mouse hepatocytes also showed decreased cell death and inhibition of sustained JNK phosphorylation following toxic APAP treatment. While SHP expression declined, GADD45β expression increased after APAP treatment in WT mice. In Shp-/- mice, APAP-evoked GADD45β induction was significantly enhanced. Notably, the ameliorative effects of SHP deficiency on APAP-induced liver injury were abolished in Shp-/-Gadd45β-/- mice. The current study is the first to demonstrate that hepatocyte-specific SHP deficiency protects against APAP overdose-evoked hepatotoxicity in a JNK signaling regulation and GADD45β dependent manner. SHP is suggested to be a novel therapeutic target for APAP overdose treatment.

KEYWORDS:

Acetaminophen; GADD45β; Hepatotoxicity; JNK; SHP

PMID:
29943110
DOI:
10.1007/s00204-018-2247-3

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