AMP-activated protein kinase agonist N-6-(3-hydroxyphenyl)adenosine protects against fulminant hepatitis by suppressing inflammation and apoptosis

文献类型： 外文期刊

第一作者： Li, Jin

作者： Li, Jin;Wang, Fengzhong;Chen, Bo;Chen, Bo;Gao, Feng;Zhu, Haibo;Zhong, Liping;Gao, Feng;Zhu, Haibo;Gao, Feng;Zhu, Haibo

作者机构：

期刊名称：CELL DEATH & DISEASE （ 影响因子：8.469； 五年影响因子：8.713 ）

ISSN： 2041-4889

年卷期： 2018 年 9 卷

页码：

收录情况： SCI

摘要： Both AMP-activated protein kinase (AMPK) agonist and inhibitor have been reported to protect against fulminant hepatitis, implying that AMPK may play a complicated role in the development of fulminant hepatitis. In this study, we exploited whether the novel AMPK agonist N-6-(3-hydroxyphenyl) adenosine (named as M1) exerted protective effects on fulminant hepatitis and whether its beneficial effects were AMPK-dependent. Results showed that intraperitoneal injection of M1 improved liver function, ameliorated liver injury and finally raised the survival rate in D-galactosamine/lipopolysaccharide (GalN/LPS)-treated mice. These beneficial effects of M1 may attribute to the suppression of pro-inflammatory cytokines production and the prevention of hepatocyte apoptosis. Furthermore, M1 pretreatment mitigated LPS-stimulated TLR4 expression and NF kappa B activation in murine peritoneal macrophages and prevented actinomycin D (Act D)/tumor necrosis factor alpha (TNF alpha)-induced apoptosis by promoting protective autophagy in primary hepatocytes. Additionally, M1-induced AMPK activation was responsible both for its anti-inflammatory action in macrophages and for its anti-apoptotic action in hepatocytes. To our surprise, compared with the control AMPK alpha 1(lox/lox)/AMPK alpha 2(lox/lox) mice, liver-specific AMPK alpha 1 knockout (AMPK alpha 1(LS)(-/-)) mice were more sensitive to GalN/LPS administration but not AMPK alpha 2(LS)(-/-) mice, and the beneficial effects of M1 on acute liver failure and the production of pro-inflammatory factors were dampened in AMPK alpha 1(LS)(-/-) mice. Therefore, our study may prove that M1 could be a promising therapeutic agent for fulminant hepatitis, and targeting AMPK may be useful therapeutically in the control of LPS-induced hepatotoxicity.

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