Identification of a natural PLA2 inhibitor from the marine fungus Aspergillus sp. c1 for MAFLD treatment that suppressed lipotoxicity by inhibiting the IRE-1a/XBP-1s axis and JNK signaling

文献类型： 外文期刊

第一作者： Rao, Yong

作者： Rao, Yong;Su, Rui;Wu, Chenyan;Yang, Guanyu;Wu, Junjie;Fu, Tingting;Jiang, Zhongping;Xu, Congjun;Huang, Ling;Guo, Zhikai;Guo, Zhikai;Li, Jinjian;Chai, Xingxing

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关键词： Lipotoxicity; MAFLD; ER stress; IRE-1a; XBP-1s; JNK; PLA2

期刊名称：ACTA PHARMACEUTICA SINICA B （ 影响因子：14.5； 五年影响因子：13.2 ）

ISSN： 2211-3835

年卷期： 2024 年 14 卷 1 期

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收录情况： SCI

摘要： Lipotoxicity is a pivotal factor that initiates and exacerbates liver injury and is involved in the development of metabolic -associated fatty liver disease (MAFLD). However, there are few reported lipotoxicity inhibitors. Here, we identified a natural anti-lipotoxicity candidate, HN-001, from the marine fungus Aspergillus sp. C 1. HN-001 dose- and time- dependently reversed palmitic acid (PA) -induced hepatocyte death. This protection was associated with IRE -1a -mediated XBP-1 splicing inhibition, which resulted in suppression of XBP-1s nuclear translocation and transcriptional regulation. Knockdown of XBP-1s attenuated lipotoxicity, but no additional ameliorative effect of HN-001 on lipotoxicity was observed in XBP-1s knockdown hepatocytes. Notably, the ER stress and lipotoxicity amelioration was associated with PLA2. Both HN-001 and the PLA2 inhibitor MAFP inhibited PLA2 activity, reduced lysophosphatidylcholine (LPC) level, subsequently ameliorated lipotoxicity. In contrast, overexpression of PLA2 caused exacerbation of lipotoxicity and weakened the anti-lipotoxic effects of HN-001. Additionally, HN-001 treatment suppressed the downstream pro-apoptotic JNK pathway. In vivo, chronic administration of HN-001 (i.p.) in mice alleviated all manifestations of MAFLD, including hepatic steatosis, liver injury, inflammation, and fibrogenesis. These effects were correlated with PLA2/IRE-1a/XBP-1s axis and JNK signaling suppression. These data indicate that HN-001 has therapeutic potential for MAFLD because it suppresses lipotoxicity, and provide a natural structural basis for developing antiMAFLD candidates. 2024 The Authors. Published by Elsevier B.V. on behalf of Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. This is an open access article under the CC BY -NCND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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