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Published in:

08-07-2022 | Original Research Article

Caffeine alleviates acute liver injury by inducing the expression of NEDD4L and deceasing GRP78 level via ubiquitination

Authors: Xing-Wang Hu, Xiang-Min Li, Ai-Min Wang, Yong-Ming Fu, Fang-Jie Zhang, Feng Zeng, Li-Ping Cao, Hui Long, Ying-Hui Xiong, Ji Xu, Jia Li

Published in: Inflammation Research | Issue 10-11/2022

Abstract

Background

Acute liver injury is liver cell injury that occurs rapidly in a short period of time. Caffeine has been shown to maintain hepatoprotective effect with an unclear mechanism. Endoplasmic reticulum stress (ERS) has significant effects in acute liver injury. Induction of GRP78 is a hallmark of ERS. Whether or not caffeine’s function is related to GRP78 remains to be explored.

Methods

Acute liver injury model was established by LPS-treated L02 cells and in vivo administration of LPS/D-Gal in mice. Caffeine was pre-treated in L02 cells or mice. Gene levels was determined by real-time PCR and western blot. Cell viability was tested by CCK-8 assay and cell apoptosis was tested by flow cytometry. The interaction of GRP78 and NEDD4L was determined by Pull-down and co-immunoprecipitation (Co-IP) assay. The ubiquitination by NEDD4L on GRP78 was validated by in vitro ubiquitination assay.

Results

Caffeine protected liver cells against acute injury induced cell apoptosis and ERS both in vitro and in vivo. Suppression of GRP78 could block the LPS-induced cell apoptosis and ERS. NEDD4L was found to interact with GRP78 and ubiquitinate its lysine of 324 site directly. Caffeine treatment induced the expression of NEDD4L, resulting in the ubiquitination and inhibition of GRP78.

Conclusion

Caffeine mitigated the acute liver injury by stimulating NEDD4L expression, which inhibited GRP78 expression via ubiquitination at its K324 site. Low dose of caffeine could be a promising therapeutic treatment for acute liver injury.

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Title: Caffeine alleviates acute liver injury by inducing the expression of NEDD4L and deceasing GRP78 level via ubiquitination
Authors: Xing-Wang Hu
Xiang-Min Li
Ai-Min Wang
Yong-Ming Fu
Fang-Jie Zhang
Feng Zeng
Li-Ping Cao
Hui Long
Ying-Hui Xiong
Ji Xu
Jia Li
Publication date: 08-07-2022
Publisher: Springer International Publishing
Published in: Inflammation Research / Issue 10-11/2022
Print ISSN: 1023-3830
Electronic ISSN: 1420-908X
DOI: https://doi.org/10.1007/s00011-022-01603-0

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Results

Conclusion

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