Hepatocyte-specific deficiency of DAX-1 protects mice from acetaminophen-induced hepatotoxicity by activating NRF2 signaling

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Title
Hepatocyte-specific deficiency of DAX-1 protects mice from acetaminophen-induced hepatotoxicity by activating NRF2 signaling
Author(s)
Young Joo Suh; Hyo Jeong Yoon; Yu-Bin Kim; Eun Jung Kang; Jung-Hyeon ChoiYoung Keun ChoiIn-Bok LeeDong Hee ChoiYun Jeong SeoJung Ran Noh; J S Lee; Yong-Hoon KimChul-Ho Lee
Bibliographic Citation
International Journal of Molecular Sciences, vol. 23, no. 19, pp. 11786-11786
Publication Year
2022
Abstract
Acetaminophen (APAP) is a widely used analgesic and antipyretic drug, but its overdose can cause acute liver failure. The dosage-sensitive sex reversal adrenal hypoplasia congenita critical region on the X chromosome, gene 1 (DAX-1, NR0B1), is an orphan nuclear receptor that acts as a transcriptional co-repressor of various genes. In this study, we identified the role of DAX-1 in APAP-induced liver injury using hepatocyte-specific Dax-1 knockout (Dax-1 LKO) mice. Mouse primary hepatocytes were used as a comparative in vitro study. APAP overdose led to decreased plasma alanine aminotransferase and aspartate aminotransferase levels in Dax-1 LKO mice compared to C57BL/6J (WT) controls, accompanied by reduced liver necrosis. The expression of the genes encoding the enzymes catalyzing glutathione (GSH) synthesis and metabolism and antioxidant enzymes was increased in the livers of APAP-treated Dax-1 LKO mice. The rapid recovery of GSH levels in the mitochondrial fraction of APAP-treated Dax-1 LKO mice led to reduced reactive oxygen species levels, resulting in the inhibition of the prolonged JNK activation. The hepatocyte-specific DAX-1 deficiency increased the protein expression of nuclear factor erythroid 2-related factor 2 (Nrf2) compared with WT controls after APAP administration. These results indicate that DAX-1 deficiency in hepatocytes protects against APAP-induced liver injury by Nrf2-regulated antioxidant defense.
Keyword
DAX-1AcetaminophenNrf2Hepatotoxicity
ISSN
1661-6596
Publisher
MDPI
DOI
http://dx.doi.org/10.3390/ijms231911786
Type
Article
Appears in Collections:
Ochang Branch Institute > Division of National Bio-Infrastructure > Laboratory Animal Resource & Research Center > 1. Journal Articles
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