Chen Tong, Shuang Ruonan, Gao Tiantian, Ai Lijun, Diao Jichen, Yuan Xinyi, He Ling, Tao Weiwei, Huang Xin
Department of Pharmacology, China Pharmaceutical University, Nanjing, China.
School of Integrated Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China.
J Pineal Res. 2024 Nov;76(8):e70010. doi: 10.1111/jpi.70010.
Melatonin (MLT) has been reported to attenuate Concanavalin A (Con A)-induced acute liver injury via the inhibition of immune cells. Whereas the response of hepatocyte to Con A-caused inflammatory storm and the mechanism of MLT on hepatocyte remain not fully understood. Our RNA-seq and bioinformatic analyses suggested that OPA1 and fatty acid β-oxidation might be critical. It was found that MLT ameliorated Con A-induced acute liver injury, promoted mitochondrial fusion, fatty acid β-oxidation, modulated metabolic reprogramming and inhibited apoptosis. The overexpression and knockdown of OPA1 by adenovirus proved that these processes were governed by OPA1. With the overexpression plasmid, agonist, inhibitor and SiRNA, we found that MLT promoted OPA1 upregulation to enhance fatty acid β-oxidation, which inhibited apoptosis. The MLT and OPA1-promoted fatty acid β-oxidation enhanced ATP production rather than reduced lipid accumulation. AMPK/FOXO1 was required for MLT and OPA1-mediated fatty acid β-oxidation and apoptosis. NOTCH1 was also necessary for this apoptotic process. The results were verified in immune deficiency mice and AML12 cells induced by Con A-stimulated monocyte supernatant. MLT might control the transcription of OPA1 through MEF2A. TOMM70 was critical for MLT translocation and OPA1 upregulation. In conclusion, the present study demonstrated that MLT attenuated Con A-induced acute liver injury via the OPA1-controlled fatty acid β-oxidation to inhibit apoptosis in hepatocyte.
据报道，褪黑素（MLT）可通过抑制免疫细胞减轻伴刀豆球蛋白A（Con A）诱导的急性肝损伤。然而，肝细胞对Con A引起的炎症风暴的反应以及MLT对肝细胞的作用机制仍未完全阐明。我们的RNA测序和生物信息学分析表明，OPA1和脂肪酸β-氧化可能至关重要。研究发现，MLT可改善Con A诱导的急性肝损伤，促进线粒体融合、脂肪酸β-氧化，调节代谢重编程并抑制细胞凋亡。通过腺病毒对OPA1进行过表达和敲低证明，这些过程受OPA1调控。利用过表达质粒、激动剂、抑制剂和小干扰RNA，我们发现MLT促进OPA1上调以增强脂肪酸β-氧化，从而抑制细胞凋亡。MLT和OPA1促进的脂肪酸β-氧化增加了ATP生成，而非减少脂质积累。MLT和OPA1介导的脂肪酸β-氧化及细胞凋亡需要AMPK/FOXO1。NOTCH1对这一凋亡过程也必不可少。在免疫缺陷小鼠和由Con A刺激的单核细胞上清液诱导的AML12细胞中验证了这些结果。MLT可能通过MEF2A控制OPA1的转录。TOMM70对MLT易位和OPA1上调至关重要。总之，本研究表明，MLT通过OPA1控制的脂肪酸β-氧化减轻Con A诱导的急性肝损伤，从而抑制肝细胞凋亡。
