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

• Main Authors: Yong Rao (Author), Rui Su (Author), Chenyan Wu (Author), Xingxing Chai (Author), Jinjian Li (Author), Guanyu Yang (Author), Junjie Wu (Author), Tingting Fu (Author), Zhongping Jiang (Author), Zhikai Guo (Author), Congjun Xu (Author), Ling Huang (Author)
• Format: Book
• Published: Elsevier, 2024-01-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.
• Notes: 2211-3835; 10.1016/j.apsb.2023.08.032
• Keywords: Lipotoxicity; MAFLD; ER stress; IRE-1α; XBP-1s; JNK; Therapeutics. Pharmacology; RM1-950
• Source: Acta Pharmaceutica Sinica B, Vol 14, Iss 1, Pp 304-318 (2024)

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.