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

• Published in: Acta pharmaceutica Sinica. B Vol. 14; no. 1; pp. 304 - 318
• Main Authors: Rao, Yong, Su, Rui, Wu, Chenyan, Chai, Xingxing, Li, Jinjian, Yang, Guanyu, Wu, Junjie, Fu, Tingting, Jiang, Zhongping, Guo, Zhikai, Xu, Congjun, Huang, Ling
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.01.2024; Elsevier
• Subjects: ER stress; IRE-1α; JNK; Lipotoxicity; MAFLD; Original; PLA2; XBP-1s; MAFLD; IRE-1α; JNK; ER stress; XBP-1s; PLA2; Lipotoxicity
• ISSN: 2211-3835; 2211-3843
• DOI: 10.1016/j.apsb.2023.08.032

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. 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. 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. [Display omitted]