ARRB1 downregulates acetaminophen-induced hepatoxicity through binding to p-eIF2α to inhibit ER stress signaling.

Autor: Luo Y; Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, People's Republic of China.; Guangdong Provincial Key Laboratory of Liver Disease Research, Guangzhou, Guangdong, People's Republic of China., Lei Y; Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, People's Republic of China.; Guangdong Provincial Key Laboratory of Liver Disease Research, Guangzhou, Guangdong, People's Republic of China., Zhou H; Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, People's Republic of China.; Guangdong Provincial Key Laboratory of Liver Disease Research, Guangzhou, Guangdong, People's Republic of China., Chen Y; Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, People's Republic of China.; Guangdong Provincial Key Laboratory of Liver Disease Research, Guangzhou, Guangdong, People's Republic of China., Liu H; Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, People's Republic of China.; Guangdong Provincial Key Laboratory of Liver Disease Research, Guangzhou, Guangdong, People's Republic of China., Jiang J; Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, People's Republic of China.; Guangdong Provincial Key Laboratory of Liver Disease Research, Guangzhou, Guangdong, People's Republic of China., Xu C; Department of Gynecology and Obstetrics, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, People's Republic of China. xuchengf@mail.sysu.edu.cn., Wu B; Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, People's Republic of China. wubin6@mail.sysu.edu.cn.; Guangdong Provincial Key Laboratory of Liver Disease Research, Guangzhou, Guangdong, People's Republic of China. wubin6@mail.sysu.edu.cn.
Jazyk: angličtina
Zdroj: Cell biology and toxicology [Cell Biol Toxicol] 2024 Jan 22; Vol. 40 (1), pp. 1. Date of Electronic Publication: 2024 Jan 22.
DOI: 10.1007/s10565-024-09842-z
Abstrakt: Acetaminophen (APAP) stands as the predominant contributor to drug-induced liver injury (DILI), and limited options are available. β-Arrestin1 (ARRB1) is involved in numerous liver diseases. However, the role of ARRB1 in APAP-induced liver injury remained uncertain. Wild-type (WT) and ARRB1 knockout (KO) mice were injected with APAP and sacrificed at the indicated times. The histological changes, inflammation, endoplasmic reticulum (ER) stress, and apoptosis were then evaluated. Hepatic cell lines AML-12 and primary hepatocytes were used for in vitro analyses. Systemic ARRB1-KO mice were susceptible to APAP-induced hepatotoxicity, as indicated by larger areas of centrilobular necrosis area and higher levels of ALT, AST, and inflammation level. Moreover, ARRB1-KO mice exhibited increased ER stress (indicated by phosphorylated α subunit of eukaryotic initiation factor 2 (p-eIF2α)-activating transcription factor 4 (ATF4)-CCAAT-enhancer-binding protein homologous protein (CHOP)) and apoptosis (indicated by cleaved caspase 3). Further rescue experiments demonstrated that the induction of apoptosis was partially mediated by ER stress. Overexpression of ARRB1 alleviated APAP-induced ER stress and apoptosis. Moreover, co-IP analysis revealed that ARRB1 directly bound to p-eIF2α and eIF2α. ARRB1 protected against APAP-induced hepatoxicity through targeting ER stress and apoptosis. ARRB1 is a prospective target for treating APAP-induced DILI.
(© 2024. The Author(s).)
Databáze: MEDLINE
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