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Regulation of monocyte activation by PPARα through interaction with the cGAS-STING pathway
Diabetes ( IF 6.2 ) Pub Date : 2023-04-14 , DOI: 10.2337/db22-0654
Lijie Dong 1, 2, 3 , Rui Cheng 2, 4 , Xiang Ma 2, 4 , Wentao Liang 2, 4 , Yaru Hong 1, 3 , Hui Li 1, 3 , Kelu Zhou 2, 4 , Yanhong Du 2 , Yusuke Takahashi 2, 4 , Xiaomin Zhang 1, 3 , Xiaorong Li 1, 3 , Jian-xing Ma 2, 4
Affiliation  

Monocyte activation plays an important role in diabetic complications such as diabetic retinopathy (DR). However, the regulation of monocyte activation in diabetes remains elusive. Fenofibrate, an agonist of peroxisome proliferator-activated receptor-alpha (PPARα), has shown robust therapeutic effects on DR in type 2 diabetic patients. Here we found that PPARα levels were significantly down-regulated in monocytes from diabetic patients and animal models, correlating with monocyte activation. Fenofibrate attenuated monocyte activation in diabetes, while PPARα knock-out alone induced monocyte activation. Furthermore, monocyte-specific PPARα overexpression ameliorated, while monocyte-specific PPARα knock-out aggravated, monocyte activation in diabetes. PPARα knock-out impaired mitochondrial function, while increasing glycolysis in monocytes. PPARα knock-out increased cytosolic mitochondrial DNA release and activation of the cGAS-STING pathway in monocytes under diabetic conditions. STING knock-out or STING inhibitor attenuated monocyte activation induced by diabetes or by PPARα knock-out. These observations suggest that PPARα negatively regulates monocyte activation through metabolic reprogramming and interaction with the cGAS-STING pathway.

中文翻译:

PPARα 通过与 cGAS-STING 通路相互作用调节单核细胞活化

单核细胞激活在糖尿病并发症如糖尿病视网膜病变 (DR) 中起重要作用。然而,糖尿病中单核细胞活化的调节仍然难以捉摸。非诺贝特是过氧化物酶体增殖物激活受体-α (PPARα) 的激动剂,对 2 型糖尿病患者的 DR 显示出强大的治疗效果。在这里,我们发现糖尿病患者和动物模型的单核细胞中 PPARα 水平显着下调,与单核细胞活化相关。非诺贝特减弱了糖尿病中的单核细胞活化,而单独敲除 PPARα 可诱导单核细胞活化。此外,单核细胞特异性 PPARα 过表达得到改善,而单核细胞特异性 PPARα 敲除加剧了糖尿病中的单核细胞活化。PPARα 敲除会损害线粒体功能,同时增加单核细胞的糖酵解。PPARα 敲除增加了糖尿病条件下单核细胞中细胞溶质线粒体 DNA 的释放和 cGAS-STING 通路的激活。STING 敲除或 STING 抑制剂减弱了由糖尿病或 PPARα 敲除诱导的单核细胞活化。这些观察结果表明,PPARα 通过代谢重编程和与 cGAS-STING 通路的相互作用负向调节单核细胞活化。
更新日期:2023-04-14
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