The transcriptional modulator Ifrd1 controls PGC-1α expression under short-term adrenergic stimulation in brown adipocytes
The transcriptional modulator Ifrd1 controls PGC-1α expression under short-term adrenergic stimulation in brown adipocytes
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DOI：
10.1111/febs.14019
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发表时间：
2017-03-01
期刊：
影响因子：
5.4
通讯作者：
Hinoi, Eiichi
中科院分区：
文献类型：
--
作者：
Park, Gyujin;Horie, Tetsuhiro;Hinoi, Eiichi
交感神经张力激活经典棕色脂肪细胞的功能，经典棕色脂肪细胞组成存在于棕色脂肪组织（BAT）中，而诱导棕色脂肪细胞（所谓的米色脂肪细胞）零星存在于白色脂肪组织（WAT）中。在这里，我们发现转录调节剂干扰素相关发育调节剂1 （Ifrd1）是棕色脂肪细胞中产热和线粒体基因表达的负调节因子。低温暴露和CL-316243（一种β 3肾上腺素能激动剂）可显著诱导Ifrd1在肩膜间棕色脂肪组织和腹股沟皮下组织中的表达，但在附睾内脏组织中不表达Ifrd1。肾上腺素能刺激也在体外以cAMP响应元件结合蛋白依赖的方式诱导褐色脂肪细胞中Ifrd1的表达。与野生型小鼠相比，注射CL-316243显著提高Ifrd1基因敲除小鼠皮下WAT中产热基因和线粒体基因的表达，包括过氧化物酶体增殖物激活受体γ辅助激活因子1 α (Pgc1 α)的表达。转录因子特异性蛋白1 （Sp1）增强的Pgc1a启动子活性在棕色脂肪细胞中被Ifrd1共同引入后明显抑制，而添加组蛋白去乙酰化酶抑制剂trichostatin A可明显阻止这种抑制。此外，肾上腺素能刺激诱导褐色脂肪细胞中Ifrd1、Sp1和mSIN3B之间形成复合物，mSIN3B是含有组蛋白去乙酰化酶的SIN复合物的一个组成部分。因此，这些发现表明，Ifrd1可能通过与Sp1和mSIN3复合物相互作用，成为棕色脂肪细胞中产热基因和线粒体基因表达的交感调节的关键负调节因子。
Sympathetic tone activates the function of classical brown adipocytes, which constitutively exist in the brown adipose tissue (BAT), and inducible brown adipocytes (so-called beige adipocytes), which sporadically reside within the white adipose tissue (WAT). Here we identified the transcriptional modulator interferon-related developmental regulator 1 (Ifrd1) as a negative regulator of thermogenic and mitochondrial gene expression in brown adipocytes. Ifrd1 expression was markedly induced by cold exposure and administration of CL-316243 (a beta 3 adrenergic agonist) in interscapular brown adipose and inguinal subcutaneous WATs, but not in epididymal visceral WAT, in vivo. Adrenergic stimulation also induced Ifrd1 expression in brown adipocytes in a cAMP responsive element binding protein-dependent manner in vitro. CL-316243 injection markedly elevated thermogenic and mitochondrial gene expression, including peroxisome proliferator-activated receptor gamma coactivator 1 alpha (Pgc1 alpha) in the subcutaneous WAT of Ifrd1 knockout mice compared with gene expression in wild-type mice. Pgc1a promoter activity enhanced by the transcription factor specificity protein 1 (Sp1) was markedly repressed by co-introduction of Ifrd1 in brown adipocytes, whereas the repression was markedly prevented by the addition of trichostatin A, a histone deacetylase inhibitor. Moreover, adrenergic stimulation induced complex formation between Ifrd1, Sp1 and mSIN3B, which is a component of the SIN complex containing histone deacetylase, in brown adipocytes. These findings, therefore, suggest that Ifrd1 could be a pivotal negative regulator of sympathetic regulation of thermogenic and mitochondrial gene expression in brown adipocytes by interacting with Sp1 and the mSIN3 complex.