Kojima Ryota, Hirata Yusuke, Ashida Ryo, Takahashi Miki, Matsui Ryosuke, Hama Kotaro, Watanabe Ayako, Takita Ryo, Sato Emiko, Abe Taiki, Yokoyama Kazuaki, Noguchi Takuya, Matsuzawa Atsushi
Laboratory of Health Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aoba, Aramaki, Aoba-ku, Sendai 980-8578, Japan.
Faculty of Pharmaceutical Sciences, Teikyo University, 2-11-1 Kaga, Itabashi-ku, Tokyo 173-8605, Japan.
iScience. 2025 Aug 6;28(9):113305. doi: 10.1016/j.isci.2025.113305. eCollection 2025 Sep 19.
Fatty acids (TFAs) have been associated with various inflammatory diseases, including atherosclerosis and metabolic syndrome, such as metabolic dysfunction-associated steatotic liver disease (MASLD)/metabolic dysfunction-associated steatohepatitis (MASH). However, the underlying mechanism remains unclear. Here, we show that in response to DNA damage, elaidic acid (EA), a most common TFA, amplifies interleukin-1 receptor (IL-1R) signaling, leading to the promotion of cellular senescence and senescence-associated secretory phenotype (SASP). Upon DNA damage, EA enhanced senescence-associated β-galactosidase activity and expressions of IL-1α/6/8 through the IL-1R-transforming growth factor-β-activated kinase 1 (TAK1)-nuclear factor (NF)-κB axis in a manner dependent on mammalian target of rapamycin (mTOR). Mechanistically, EA, incorporated into lipid rafts, enhances IL-1R activation and subsequent NF-κB signaling, creating a positive feedback loop. EA consumption elevated expressions of SASP factors and cellular senescence in the livers of high-fat diet mice. Our findings provide a mechanistic insight into TFA-related inflammation and disorders, including MASLD/MASH.
反式脂肪酸（TFAs）与多种炎症性疾病有关，包括动脉粥样硬化和代谢综合征，如代谢功能障碍相关脂肪性肝病（MASLD）/代谢功能障碍相关脂肪性肝炎（MASH）。然而，其潜在机制仍不清楚。在此，我们表明，在DNA损伤反应中，最常见的反式脂肪酸——反油酸（EA）会放大白细胞介素-1受体（IL-1R）信号，导致细胞衰老和衰老相关分泌表型（SASP）的促进。在DNA损伤时，EA通过IL-1R-转化生长因子-β激活激酶1（TAK1）-核因子（NF）-κB轴，以依赖雷帕霉素靶蛋白（mTOR）的方式增强衰老相关β-半乳糖苷酶活性以及IL-1α/6/8的表达。从机制上讲，掺入脂筏的EA增强IL-1R激活及随后的NF-κB信号传导，形成一个正反馈回路。在高脂饮食小鼠的肝脏中，EA的摄入增加了SASP因子的表达和细胞衰老。我们的研究结果为TFAs相关的炎症和疾病，包括MASLD/MASH，提供了一个机制性的见解。
