Liu Zhenjiang, Gu Huihui, Gan Lu, Xu Yatao, Feng Fei, Saeed Muhammad, Sun Chao
College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, 712100, China.
Oncotarget. 2017 Feb 7;8(6):9267-9279. doi: 10.18632/oncotarget.14035.
Sirtuin 1 (Sirt1) promotes adaptive thermogenesis by controlling the acetylation status of enzymes and transcriptional factors in interscapular brown adipose tissue (iBAT). However, the effects of Sirt1 on endoplasmic reticulum (ER) stress and apoptosis of iBAT remain elusive. In this study, the mRNA levels of Sirt1 and thermogenesis genes were reduced but the genes related with ER stress were elevated in iBAT of high-fat diet (HFD)-induced obese mice. Moreover, ER stress further inhibited mRNA level of Sirt1 and triggered brown adipocyte apoptosis in vitro and in vivo. Further analysis revealed that Sirt1 overexpression alleviated ER stress-induced brown adipocyte apoptosis by inhibiting Smad3 and ATF4. In addition, Smad3 bound to ATF4 promoter region and positively transcriptional regulation of ATF4. Our data also confirmed that Sirt1 reduced early apoptotic cells and blocked the mitochondrial apoptosis pathway by directly interacting with ATF4. Furthermore, Sirt1 attenuated tunicamycin-induced cold intolerance and elevating thermogenesis by inhibiting ER stress and apoptosis in iBAT. In summary, our data collectively revealed Sirt1 reduced ER stress and apoptosis of brown adipocyte in vivo and in vitro by inhibiting Smad3/ATF4 signal. These data reveal a novel mechanism that links Sirt1 to brown adipocyte apoptosis.
沉默调节蛋白1（Sirt1）通过控制肩胛间棕色脂肪组织（iBAT）中酶和转录因子的乙酰化状态来促进适应性产热。然而，Sirt1对iBAT内质网（ER）应激和凋亡的影响仍不清楚。在本研究中，高脂饮食（HFD）诱导的肥胖小鼠的iBAT中，Sirt1和产热基因的mRNA水平降低，但与ER应激相关的基因升高。此外，ER应激在体外和体内进一步抑制Sirt1的mRNA水平并引发棕色脂肪细胞凋亡。进一步分析表明，Sirt1过表达通过抑制Smad3和ATF4减轻ER应激诱导的棕色脂肪细胞凋亡。此外，Smad3与ATF4启动子区域结合并对ATF4进行正向转录调控。我们的数据还证实，Sirt1通过直接与ATF4相互作用减少早期凋亡细胞并阻断线粒体凋亡途径。此外，Sirt1通过抑制iBAT中的ER应激和凋亡减轻衣霉素诱导的耐寒性并提高产热。总之，我们的数据共同表明，Sirt1通过抑制Smad3/ATF4信号在体内和体外减少棕色脂肪细胞的ER应激和凋亡。这些数据揭示了一种将Sirt1与棕色脂肪细胞凋亡联系起来的新机制。
