研究揭示IL-1抑制脂肪細胞氧化代謝的分子機制
作者：
小柯機器人發布時間：2020/8/13 16:45:30
美國克利夫蘭診所Xiaoxia Li研究小組的最新發現表明，IL-1誘導IRAK2線粒體易位，從而抑制脂肪細胞的氧化代謝。相關論文於2020年8月10日在線發表在《自然—免疫學》雜誌上。
研究人員報導了一個非經典的IL-1R–MyD88–IRAK2–PHB/OPA1信號轉導軸，其可重新編程脂肪細胞中的線粒體代謝，從而加劇肥胖。IL-1通過TOM20的識別誘導IRAK2 Myddosome募集到線粒體外膜，然後TIMM50引導IRAK2易位到線粒體內膜，從而抑制氧化磷酸化和脂肪酸氧化，進而減少能量消耗。脂肪細胞特異性MyD88或IRAK2缺失減少了高脂肪飲食誘導的體重增加，增加了能量消耗，改善了胰島素抵抗，並伴有較小的脂肪細胞尺寸和線粒體嵴形成增加。IRAK2激酶失活也減少了高脂飲食誘導的代謝疾病。
從機理上講，IRAK2在刺激IL-1時通過與PHB1和OPA1相互作用來抑制呼吸超複合物的形成。總之，這些結果表明IRAK2 Myddosome是炎症和代謝之間的關鍵環節，並且是肥胖患者的新型治療靶點。
據了解，慢性炎症是肥胖症的常見特徵，其循環和組織中的細胞因子升高，比如IL-1。
附：英文原文
Title: IL-1 induces mitochondrial translocation of IRAK2 to suppress oxidative metabolism in adipocytes
Author: Hao Zhou, Han Wang, Minjia Yu, Rebecca C. Schugar, Wen Qian, Fangqiang Tang, Weiwei Liu, Hui Yang, Ruth E. McDowell, Junjie Zhao, Ji Gao, Ashok Dongre, Julie A. Carman, Mei Yin, Judith A. Drazba, Robert Dent, Christopher Hine, Yeong-Renn Chen, Jonathan D. Smith, Paul L. Fox, J. Mark Brown, Xiaoxia Li
Issue&Volume: 2020-08-10
Abstract: Chronic inflammation is a common feature of obesity, with elevated cytokines such as interleukin-1 (IL-1) in the circulation and tissues. Here, we report an unconventional IL-1R–MyD88–IRAK2–PHB/OPA1 signaling axis that reprograms mitochondrial metabolism in adipocytes to exacerbate obesity. IL-1 induced recruitment of IRAK2 Myddosome to mitochondria outer membranes via recognition by TOM20, followed by TIMM50-guided translocation of IRAK2 into mitochondria inner membranes, to suppress oxidative phosphorylation and fatty acid oxidation, thereby attenuating energy expenditure. Adipocyte-specific MyD88 or IRAK2 deficiency reduced high-fat-diet-induced weight gain, increased energy expenditure and ameliorated insulin resistance, associated with a smaller adipocyte size and increased cristae formation. IRAK2 kinase inactivation also reduced high-fat diet-induced metabolic diseases. Mechanistically, IRAK2 suppressed respiratory super-complex formation via interaction with PHB1 and OPA1 upon stimulation of IL-1. Taken together, our results suggest that the IRAK2 Myddosome functions as a critical link between inflammation and metabolism, representing a novel therapeutic target for patients with obesity.
DOI: 10.1038/s41590-020-0750-1
Source: https://www.nature.com/articles/s41590-020-0750-1