Hepatocyte-Specific Deficiency of DAX-1 Protects Mice from Acetaminophen-Induced Hepatotoxicity by Activating NRF2 Signaling
| Autor: | Young-Joo Suh, Hyo-Jeong Yun, Yu-Bin Kim, Eun-Jung Kang, Jung Hyeon Choi, Young-Keun Choi, In-Bok Lee, Dong-Hee Choi, Yun Jeong Seo, Jung-Ran Noh, Jong-Soo Lee, Yong-Hoon Kim, Chul-Ho Lee |
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| Rok vydání: | 2022 |
| Předmět: |
Antipyretics
NF-E2-Related Factor 2 Antioxidants Catalysis Inorganic Chemistry Mice Animals Aspartate Aminotransferases Physical and Theoretical Chemistry Molecular Biology Spectroscopy Acetaminophen Mice Knockout DAX-1 Orphan Nuclear Receptor Organic Chemistry Alanine Transaminase General Medicine Orphan Nuclear Receptors Glutathione Computer Science Applications Mice Inbred C57BL DAX-1 acetaminophen Nrf2 hepatotoxicity Liver Hepatocytes Chemical and Drug Induced Liver Injury Reactive Oxygen Species Co-Repressor Proteins |
| Zdroj: | International Journal of Molecular Sciences; Volume 23; Issue 19; Pages: 11786 |
| ISSN: | 1422-0067 |
| DOI: | 10.3390/ijms231911786 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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