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GADD45α alleviates acetaminophen-induced hepatotoxicity by promoting AMPK activation

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Abstract

As an analgesic and antipyretic drug, acetaminophen (APAP) is commonly used and known to be safe at therapeutic doses. In many countries, the overuse of APAP provokes acute liver injury and even liver failure. APAP-induced liver injury (AILI) is the most used experimental model of drug-induced liver injury (DILI). Here, we have demonstrated elevated levels of growth arrest and DNA damage-inducible 45α (GADD45α) in the livers of patients with DILI/AILI, in APAP-injured mouse livers and in APAP-treated hepatocytes. GADD45α exhibited a protective effect against APAP-induced liver injury and alleviated the accumulation of small lipid droplets in vitro and in vivo. We found that GADD45α promoted the activation of AMP-activated protein kinase α and induced fatty acid beta-oxidation, tricarboxylic acid cycle (TCA) and glycogenolysis-related gene expression after APAP exposure. Liquid chromatography–mass spectrometry (LC–MS) analysis showed that GADD45α increased the levels of TCA cycle metabolites. Co-immunoprecipitation analysis showed that Ppp2cb, a catalytic subunit of protein phosphatase 2A, could interact directly with GADD45α. Our results indicate that hepatocyte GADD45α might represent a therapeutic target to prevent and rescue liver injury caused by APAP.

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Acknowledgements

This work was supported by the Major Project of National Twelfth Five Plan (2012ZX09303-001), the Major Project of National Thirteenth Five Plan (2017ZX09304016), the National Natural Science Foundation of China (NSFC 81670524, NSFC 31771308), the Shanghai Municipal Natural Science Foundation (17ZR1401800) and the Clinical Research Center at Shanghai Jiao Tong University School of Medicine. The funders had no role in the study design, data collection and analysis, decision to publish or manuscript preparation.

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  1. Chunmin Li and Yanan Ming contributed equally.

Authors and Affiliations

  1. Division of Gastroenterology and Hepatology, School of Medicine, Shanghai Institute of Digestive Disease, Renji Hospital, Shanghai Jiao Tong University, Shanghai, China

    Chunmin Li, Yanan Ming, Yingyue Tang, Xiaohong Lei & Yimin Mao

  2. Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China

    Dongke Xu & Xiaobo Li

  3. Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan, China

    Zhengyang Wang

  4. Department of Hepatology, Mengchao Hepatobiliary Hospital, Fujian Medical University, Fuzhou, Fujian, China

    Qingling Xu & Lvfeng Yao

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Li, C., Ming, Y., Wang, Z. et al. GADD45α alleviates acetaminophen-induced hepatotoxicity by promoting AMPK activation. Cell. Mol. Life Sci. 76, 129–145 (2019). https://doi.org/10.1007/s00018-018-2912-y

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