Histone demethylase UTX aggravates acetaminophen overdose induced hepatotoxicity through dual mechanisms. (January 2022)

• Record Type: Journal Article
• Authors: Huang, Yixue; Xie, Yunhao; Yang, Dong; Xiong, Mingrui; Chen, Xingrui; Wu, Di; Wang, Qing; Chen, Hong; Zheng, Ling; Huang, Kun
• Is Part Of: Pharmacological research. Volume 175(2022)
• Publication Date: 2022-01
• Subjects: Acetaminophen (PubChem CID: 1983) -- N-acetyl-p-benzoquinone imine (PubChem CID: 39763) -- Malondialdehyde (PubChem CID: 10964) -- Glutathione (PubChem CID: 124886); APAP acetaminophen -- ALF acute liver failure -- NAC N-acetylcysteine -- UGT UDP-glucuronosyltransferase -- SULT sulfotransferase -- GSH glutathione -- GST glutathione S-transferase -- NAPQI N-acetyl-p-benzoquinone imine -- ER endoplasmic reticulum -- UPR unfolded protein response -- PBS phosphate-buffered saline -- ALT alanine aminotransferase -- AST aspartate aminotransferase -- MDA malondialdehyde -- ROS reactive oxygen species; Utx -- Acetaminophen -- Sult2a1 -- Endoplasmic reticulum stress -- Oxidative stress; Pharmacology -- Periodicals; Pharmacology -- Periodicals; Research -- Periodicals; Médicaments -- Recherche -- Périodiques; Pharmacologie -- Périodiques; 615.105
• DOI: 10.1016/j.phrs.2021.106021
• Languages: English
• ISSNs: 1043-6618

Abstract

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. Graphical Abstract: ga1 Highlights: 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.