Histone demethylase UTX aggravates acetaminophen overdose induced hepatotoxicity through dual mechanisms
Histone demethylase UTX aggravates acetaminophen overdose induced hepatotoxicity through dual mechanisms
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组蛋白去甲基化酶UTX通过双重机制加重对乙酰氨基酚过量引起的肝毒性
DOI：
10.1016/j.phrs.2021.106021
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发表时间：
2022-01-01
影响因子：
9.3
通讯作者：
Huang, Kun
中科院分区：
文献类型：
--
作者：
Huang, Yixue;Xie, Yunhao;Huang, Kun
对乙酰氨基酚（APAP）过量是急性肝功能衰竭的主要原因，而APAP肝毒性的潜在机制尚未完全了解。最近，新的证据表明表观遗传酶在APAP诱导的肝损伤中起作用。在这里，我们发现Utx（普遍转录的tetratricopeptide repeat，X染色体，也称为KDM 6A），一种X-连锁的组蛋白去甲基化酶，从组蛋白H3 K27中去除二-和三甲基基团，在APAP过量的雌性小鼠的肝脏中被显著诱导。肝脏缺失Utx抑制APAP过量诱导的雌性小鼠肝毒性，但对雄性小鼠无抑制作用。RNA测序分析表明，在雌性小鼠中，Utx缺乏上调抗毒II相结合酶，包括磺基转移酶家族2A成员1（Sult 2a 1），从而减少损伤肝脏中毒性APAP代谢物的量;而Utx缺乏还通过下调ER应激基因（包括Atf 4，Atf 3和Chop）的转录来减轻ER应激。从机制上讲，Utx促进ER应力相关基因的转录在一个脱甲基酶活性依赖的方式，而抑制Sult 2a 1的表达，通过介导H3 K27 ac水平独立于其脱甲基酶活性。此外，Sult 2a 1在雌性小鼠肝脏中的过表达挽救了APAP过量诱导的肝损伤。总之，我们的研究结果表明了一种新的UTX-Sult 2a 1轴用于预防或治疗APAP诱导的肝损伤。
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 trimethyl 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.