1. Adenosine kinase protects against acetaminophen-induced acute liver injury by activating autophagy in hepatocytes.
- Author
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Zhang, Chuanxin, Liu, Xuehao, Liu, Xilong, Hua, Rui, Liu, Han, Ma, Jiaxin, Zou, Dan, Wang, Guangmei, Yuan, Qiuhuan, Wang, Bailu, Wei, Shujian, and Chen, Yuguo
- Subjects
ASPARTATE aminotransferase ,AMP-activated protein kinases ,PROTEIN kinases ,ADENOSINES ,LABORATORY mice - Abstract
Acute liver injury (ALI) is a common life-threatening condition with a high mortality rate due to liver disease-related death. However, current therapeutic interventions for ALI remain ineffective, and the development of effective novel therapies is urgently needed. Liver samples from patients with drug-induced ALI were collected to detect adenosine kinase (ADK) expression. Male C57BL/6 J mice, hepatocyte-specific ADK knockout (ADK
HKO ) mice, and their controls (ADKf/f ) were exposed to acetaminophen (APAP) and other treatments to investigate the mechanisms of APAP-related ALI. ADK expression was significantly decreased in APAP-injured livers. Hepatocyte-specific ADK deficiency exacerbated APAP-induced ALI, while a gain-of-function approach delivering AAV-ADK, markedly alleviated APAP-induced ALI, as indicated by changes in alanine aminotransferases (ALT) levels, aspartate aminotransferase (AST) levels, neutrophil infiltration and hepatocyte death. This study showed that ADK played a critical role in ALI by activating autophagy through two signaling pathways, the adenosine monophosphate-activated protein kinase (AMPK)-mTOR pathway and the adenosine receptor A1 (ADORA1)-Akt-mTOR pathway. Furthermore, we found that metformin upregulated ADK expression in hepatocytes and protected against APAP-induced ALI. These results demonstrate that ADK is critical in protecting against APAP-induced ALI and that developing therapeutics targeting ADK-adenosine-ADORA1 is a new approach for ALI treatment. Metformin is a potential candidate for preventing ALI by upregulating ADK. [ABSTRACT FROM AUTHOR]- Published
- 2024
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