Department of Metabolism and Endocrinology, Metabolic Syndrome Research Center, Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China.
Department of Pharmacology, University of Texas Health at San Antonio, San Antonio, TX 78229.
Proc Natl Acad Sci U S A. 2017 Nov 14;114(46):12196-12201. doi: 10.1073/pnas.1708744114. Epub 2017 Oct 30.
Chronic inflammation in adipose tissue plays a key role in obesity-induced insulin resistance. However, the mechanisms underlying obesity-induced inflammation remain elusive. Here we show that obesity promotes mtDNA release into the cytosol, where it triggers inflammatory responses by activating the DNA-sensing cGAS-cGAMP-STING pathway. Fat-specific knockout of disulfide-bond A oxidoreductase-like protein (DsbA-L), a chaperone-like protein originally identified in the mitochondrial matrix, impaired mitochondrial function and promoted mtDNA release, leading to activation of the cGAS-cGAMP-STING pathway and inflammatory responses. Conversely, fat-specific overexpression of DsbA-L protected mice against high-fat diet-induced activation of the cGAS-cGAMP-STING pathway and inflammation. Taken together, we identify DsbA-L as a key molecule that maintains mitochondrial integrity. DsbA-L deficiency promotes inflammation and insulin resistance by activating the cGAS-cGAMP-STING pathway. Our study also reveals that, in addition to its well-characterized roles in innate immune surveillance, the cGAS-cGAMP-STING pathway plays an important role in mediating obesity-induced metabolic dysfunction.
脂肪组织中的慢性炎症在肥胖引起的胰岛素抵抗中起着关键作用。然而，肥胖引起炎症的机制仍不清楚。在这里，我们表明肥胖会促进线粒体 DNA 释放到细胞质中，在线粒体 DNA 释放到细胞质中后，它通过激活 DNA 感应 cGAS-cGAMP-STING 途径触发炎症反应。脂肪特异性敲除二硫键 A 氧化还原酶样蛋白（DsbA-L），一种最初在线粒体基质中发现的伴侣样蛋白，会损害线粒体功能并促进线粒体 DNA 释放，从而激活 cGAS-cGAMP-STING 途径和炎症反应。相反，脂肪特异性过表达 DsbA-L 可防止高脂肪饮食诱导的 cGAS-cGAMP-STING 途径和炎症的激活。总之，我们确定 DsbA-L 是维持线粒体完整性的关键分子。DsbA-L 缺乏通过激活 cGAS-cGAMP-STING 途径促进炎症和胰岛素抵抗。我们的研究还表明，除了其在先天免疫监测中的特征性作用外，cGAS-cGAMP-STING 途径在介导肥胖引起的代谢功能障碍方面也起着重要作用。
