期刊
FREE RADICAL BIOLOGY AND MEDICINE
卷 153, 期 -, 页码 89-102出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.freeradbiomed.2020.03.031
关键词
Alcoholic liver disease; Hepatocyte; Mitofusin 2; Oroxylin A; Proliferator-activated receptor gamma; coactivator 1 alpha; Pyroptosis
资金
- National Natural Science Foundation of China [81270514, 31571455, 31401210, 31600653, 81600483]
- Open Project Program of Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica [JKLPSE201804, JKLPSE201815]
- Project of the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD)
- Postgraduate Research& Practice Innovation Program of Jiangsu Province [KYCX19_1264]
Background: It is well acknowledged that alcoholic liver disease (ALD) is widely prevalent all over the world, characterized by aberrant lipid deposition and excessive oxidative stress in hepatocytes. Recently, pyroptosis, a new type of programmed cell death, has been found in ALD, which provides new ideas for the treatment of ALD. Methods: Male ICR mice were treated with the Lieber-De-Carli diet (Dyets) or isocaloric liquid diet for 8 weeks, and binge alcohol model was also used for ALD. Blood and livers were taken to evaluate the efficacy of oroxylin A. The levels of factors related to hepatocyte pyroptosis were measured via western blot analyses, immuno-fluorescence analyses and quantitative reverse transcriptase in vitro. Result: Our study found that oroxylin A suppressed hepatocyte pyroptosis through a NLRP3 inflammasome dependent-canonical caspase-1 pathway. Results illuminated that oroxylin A inhibited NLRP3 inflammasome activation by reducing ROS accumulation. Furthermore, oroxylin A upregulated mitofusin 2 (Mfn2) to resist lipid deposition and mitochondria-derived ROS overproduction. As an upstream mediator of Mfn2, peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1 alpha), a major regulator of mitochondria, was found to promote transcription of Mfn2 under oroxylin A treatment. Conclusion: Our research revealed that oroxylin A could alleviate ALD via PGC-1 alpha/Mfn2 signaling mediated canonical pyroptosis pathway resistance.
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