1. Histone demethylase UTX aggravates acetaminophen overdose induced hepatotoxicity through dual mechanisms.
- Author
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Huang, Yixue, Xie, Yunhao, Yang, Dong, Xiong, Mingrui, Chen, Xingrui, Wu, Di, Wang, Qing, Chen, Hong, Zheng, Ling, and Huang, Kun
- Subjects
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DEMETHYLASE , *X chromosome , *DRUG overdose , *HEPATOTOXICOLOGY , *ACETAMINOPHEN , *SULFOTRANSFERASES , *LIVER failure , *NALOXONE - Abstract
Acetaminophen (APAP) overdose is a major cause of acute liver failure, while the underlying mechanisms of APAP hepatotoxicity are not fully understood. Recently, emerging evidence suggests that epigenetic enzymes play roles in APAP-induced liver injury. Here, we found that Utx (ubiquitously transcribed tetratricopeptide repeat, X chromosome, also known as KDM6A), a X-linked histone demethylase which removes the di- and tri-methyl groups from histone H3K27, was markedly induced in the liver of APAP-overdosed female mice. Hepatic deletion of Utx suppressed APAP overdose-induced hepatotoxicity in female but not male mice. RNA-sequencing analysis suggested that Utx deficiency in female mice upregulated antitoxic phase II conjugating enzymes, including sulfotransferase family 2 A member 1 (Sult2a1), thus reduces the amount of toxic APAP metabolites in injured liver; while Utx deficiency also alleviated ER stress through downregulating transcription of ER stress genes including Atf4 , Atf3 , and Chop. Mechanistically, Utx promoted transcription of ER stress related genes in a demethylase activity-dependent manner, while repressed Sult2a1 expression through mediating H3K27ac levels independent of its demethylase activity. Moreover, overexpression of Sult2a1 in the liver of female mice rescued APAP-overdose induced liver injury. Together, our results indicated a novel UTX-Sult2a1 axis for the prevention or treatment of APAP-induced liver injury. [Display omitted] • Utx is induced in the liver of female mouse upon APAP overdose. • Loss of Utx suppresses APAP-induced liver injury in female but not male mouse. • Utx gender-specifically regulates antitoxic phase II conjugating enzyme Sult2a1. • Utx demethylase-dependently induces ER stress and represses Sult2a1 independently. • Overexpression of Sult2a1 rescues APAP-induced hepatotoxicity in female mouse. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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