Int J Biol Sci 2022; 18(9):3800-3817. doi:10.7150/ijbs.71781 This issue

Research Paper

Egr1 confers protection against acetaminophen‑induced hepatotoxicity via transcriptional upregulating of Acaa2

Xiaohong Lei1#, Qingling Xu3#, Chunmin Li1,4#, Baolin Niu2, Yanan Ming1, Jing Li1, Yingyue Tang1,5, Xiaoyun Li1, Jieting Tang1, Jing Wu6, Yi Ju2, Lvfeng Yao3, Bin Wang3,7, Qi Miao1, Wei Zhong1, Yang Zhi1, Lirong Xu2,8, Chaojun Li9✉, Xiaobo Li2✉, Yimin Mao1✉

1. Division of Gastroenterology and Hepatology; Shanghai Institute of Digestive Disease; NHC Key Laboratory of Digestive Diseases; Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200001, China.
2. Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China
3. Department of Hepatology, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian, 350025, China
4. Department of Gastroenterology and Hepatology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China
5. Institute of Pathology, University Hospital Heidelberg, Heidelberg, 69120, Germany
6. Model Animal Research Centre (MARC), Medical School of Nanjing University, National Resource Centre for Mutant Mice, Nanjing, 210093, China
7. Department of Pathology, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, Fujian, 350122, China
8. Department of Pathology, School of Basic Medical Science, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
9. State Key Laboratory of Reproductive Medicine, Centre for Global Health, School of Public Health, Nanjing Medical University, Nanjing, 211100, China
# Xiaohong Lei, Qingling Xu and Chunmin Li contributed equally.

This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.
Citation:
Lei X, Xu Q, Li C, Niu B, Ming Y, Li J, Tang Y, Li X, Tang J, Wu J, Ju Y, Yao L, Wang B, Miao Q, Zhong W, Zhi Y, Xu L, Li C, Li X, Mao Y. Egr1 confers protection against acetaminophen‑induced hepatotoxicity via transcriptional upregulating of Acaa2. Int J Biol Sci 2022; 18(9):3800-3817. doi:10.7150/ijbs.71781. Available from https://www.ijbs.com/v18p3800.htm

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Abstract

Graphic abstract

Background: Acetaminophen (APAP)-induced liver injury (AILI) is a common cause of drug-induced liver injury (DILI). The mechanism underlying protection in AILI or DILI remains to be elucidated, and the role of early growth response 1 (Egr1) in AILI and potential mechanisms remain to be known.

Methods: The role of Egr1 was studied both in vivo and in vitro. Liver-specific Egr1-knockout (Egr1LKO) mice and those overexpressing Egr1 via tail vein injection of Egr1-expressing adenovirus (Ad-Egr1) were utilized with AILI. Chromatin immunoprecipitation-sequencing, RNA-sequencing, seahorse XF analysis, and targeted fatty acid analysis were performed. EGR1 levels were also studied in liver tissues and serum samples from AILI/DILI patients.

Results: In this study, we have demonstrated that Egr1 was upregulated in AILI models in vivo and in vitro. liver-specific Egr1 knockout aggravated AILI; however, Ad-Egr1 treatment ameliorated this. Mechanistically, Egr1 deficiency inhibited, whereas overexpression promoted, mitochondrial respiratory function and fatty acid β-oxidation (FAO) activity in AILI. Egr1 transcriptionally upregulated FAO-related genes in hepatocytes. Notably, the knockdown of acetyl-coenzyme A acyltransferase 2 (Acaa2), a key gene involved in FAO, diminished this protective effect of Egr1. Clinically, EGR1 was markedly increased in liver tissues from AILI patients. Interestingly, EGR1 levels of liver tissues and serum samples were also obviously higher in idiosyncratic DILI patients.

Conclusions: Egr1 confers adaptive protection in AILI, mediated via the transcriptional upregulation of Acaa2, which improves mitochondrial FAO, and might be a potential biomarker and novel therapeutic target for AILI.

Keywords: Acetaminophen-induced liver injury, Drug-induced liver injury, Early growth response 1, fatty acid β-oxidation