The role of ER stress and ATP/AMPK in oxidative stress meditated hepatotoxicity induced by citrinin

文献类型： 外文期刊

第一作者： Wu, Jing

作者： Wu, Jing;Yang, Chenglin;Yang, Mengran;Wu, You;Kong, Xiangyi;Fan, Hui;Wang, Siqi;Ning, Can;Xiao, Wenguang;Yi, Jine;Yuan, Zhihang;Wu, Jing;Yang, Chenglin;Yang, Mengran;Wu, You;Kong, Xiangyi;Fan, Hui;Wang, Siqi;Ning, Can;Xiao, Wenguang;Yi, Jine;Yuan, Zhihang;Liang, Zengenni;Jin, Ye

作者机构：

关键词： Citrinin; ROS; ER stress; AMPK; Cell cycle arrest; Apoptosis

期刊名称：ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY （ 影响因子：7.129； 五年影响因子：7.284 ）

ISSN： 0147-6513

年卷期： 2022 年 237 卷

页码：

收录情况： SCI

摘要： Citrinin, a secondary metabolite, can pose serious risks to the environment and organisms, but its hepatotoxic mechanisms are still unclear. Histopathological and ultrastructural results showed that citrinin-induced liver injury in Kunming mice, and the mechanism of citrinin-induced hepatotoxicity was studied in L02 cells. Firstly, citrinin mades L02 cell cycle arrest in G2/M phase by inhibition of cyclin B1, cyclin D1, cyclin-dependent kinases 2 (CDK2), and CDK4 expression. Secondly, citrinin inhibits proliferation and promotes apoptosis of L02 cells via disruption of mitochondria membrane potential, increase Bax/Bcl-2 ration, activation of caspase-3, 9, and enhance lactate dehydrogenase (LDH) release. Then, citrinin inhibits superoxide dismutase (SOD) activity and increases the accumulation of malondialdehyde (MDA) and reactive oxygen species (ROS), resulting oxidative damage in L02 cells; upregulates the protein expression of binding immunoglobulin protein (Bip), C/EBP homologous protein (CHOP), PKR-like ER kinase (PERK) and activating transcription factor6 (ATF6), inducing ER stress in L02 cells; increases the phosphorylation of AMP-activated protein kinase (AMPK) and decreases the content of adenosine-triphosphate (ATP), activating AMPK pathway in L02 cells. Eventually, pretreatment with NAC, an ROS inhibitor, alleviates citrinin-induced cell cycle G2/M arrest and apoptosis by inhibiting ROSmediated ER stress; pretreatment with 4-PBA, an ER stress inhibitor, reversed ER stress and p-AMPK; pretreatment with dorsomorphin, an AMPK inhibitor, decreases citrinin-induced cell cycle G2/M arrest and apoptosis. In summary, citrinin induces cell cycle arrest and apoptosis to aggravate liver injury by activating ROS-ER stressAMPK signaling pathway.

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