https://doi.org/10.1016/j.apsb.2023.08.032
This new article publication from Acta Pharmaceutica Sinica B, discusses the identification of a natural PLA2 inhibitor from the marine fungus Aspergillus sp. c1 for MAFLD treatment that suppressed lipotoxicity by inhibiting the IRE-1α/XBP-1s axis and JNK signaling.
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.
The authors of this article identified a natural anti-lipotoxicity candidate, HN-001, from the marine fungus Aspergillus sp. C1. HN-001 dose- and time- dependently reversed palmitic acid (PA)-induced hepatocyte death. This protection was associated with IRE-1α-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-1α/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 anti-MAFLD candidates.
Keywords: Lipotoxicity, MAFLD, ER stress, IRE-1α, XBP-1s, JNK, PLA2
Graphical Abstract: available at https://ars.els-cdn.com/content/image/1-s2.0-S2211383523003398-ga1_lrg.jpg
The identified marine fungus metabolite HN-001 ameliorates lipotoxicity by suppressing IRE-1α/XBP-1s axis and JNK pathway for MAFLD treatment with PLA2 as an upstream target.
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The Journal of the Institute of Materia Medica, the Chinese Academy of Medical Sciences and the Chinese Pharmaceutical Association.
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CiteScore: 19.4
Impact Factor: 14.5
JIF without self-citation: 13.7
ISSN 2211-3835
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Yong Rao, Rui Su, Chenyan Wu, Xingxing Chai, Jinjian Li, Guanyu Yang, Junjie Wu, Tingting Fu, Zhongping Jiang, Zhikai Guo, Congjun Xu, Ling Huang, Identification of a natural PLA2 inhibitor from the marine fungus Aspergillus sp. c1 for MAFLD treatment that suppressed lipotoxicity by inhibiting the IRE-1α/XBP-1s axis and JNK signaling, Acta Pharmaceutica Sinica B, Volume 14, Issue 1, 2024, Pages 304-318, ISSN 2211-3835, https://doi.org/10.1016/j.apsb.2023.08.032