Peroxisome Proliferator-activated Receptor-γ Coactivator-1α Controls Transcription of the Sirt3 Gene, an Essential Component of the Thermogenic Brown Adipocyte Phenotype
Peroxisome Proliferator-activated Receptor-γ Coactivator-1α Controls Transcription of the Sirt3 Gene, an Essential Component of the Thermogenic Brown Adipocyte Phenotype
复制标题
DOI：
10.1074/jbc.m110.202390
复制
发表时间：
2011-05-13
影响因子：
4.8
通讯作者：
Villarroya, Francesc
中科院分区：
文献类型：
--
作者：
Giralt, Albert;Hondares, Elayne;Villarroya, Francesc
Sirt3（沉默交配型信息调节 2，同源物 3）是蛋白质脱乙酰酶沉默调节蛋白家族的成员，对代谢和基因表达具有多种作用，其表达与棕色脂肪细胞分化相关。使用Sirt3无效的棕色脂肪细胞，我们确定Sirt3是细胞对去甲肾上腺素能、cAMP介导的棕色脂肪组织生热基因表达激活的适当反应所必需的。转录共激活因子 Pgc-1 α（过氧化物酶体增殖物激活受体-γ 共激活因子-1 α）诱导白色脂肪细胞和胚胎成纤维细胞中的 Sirt3 基因表达，作为其总体诱导棕色脂肪组织特异性基因表达模式的一部分。在缺乏 Sirt3 的细胞中，Pgc-1 α 未能完全诱导棕色脂肪特异性产热基因的表达。 Pgc-1 alpha 通过共激活孤儿核受体 Err（雌激素相关受体）-alpha 来激活 Sirt3 基因转录，该受体与近端 Sirt3 基因启动子区域结合。 Err α 敲除测定表明 Err α 是完全诱导 Sirt3 基因表达响应 Pgc-1 α 所必需的。目前的结果表明，Pgc-1 α 控制 Sirt3 基因表达，并且这种作用是 Pgc-1 α 诱导棕色脂肪细胞分化表型完全获得的整体机制的重要组成部分。
Sirt3 (silent mating type information regulation 2, homolog 3), a member of the sirtuin family of protein deacetylases with multiple actions on metabolism and gene expression is expressed in association with brown adipocyte differentiation. Using Sirt3-null brown adipocytes, we determined that Sirt3 is required for an appropriate responsiveness of cells to noradrenergic, cAMP-mediated activation of the expression of brown adipose tissue thermogenic genes. The transcriptional coactivator Pgc-1 alpha (peroxisome proliferator-activated receptor-gamma coactivator-1 alpha) induced Sirt3 gene expression in white adipocytes and embryonic fibroblasts as part of its overall induction of a brown adipose tissue-specific pattern of gene expression. In cells lacking Sirt3, Pgc-1 alpha failed to fully induce the expression of brown fat-specific thermogenic genes. Pgc-1 alpha activates Sirt3 gene transcription through coactivation of the orphan nuclear receptor Err (estrogen-related receptor)-alpha, which bound the proximal Sirt3 gene promoter region. Err alpha knockdown assays indicated that Err alpha is required for full induction of Sirt3 gene expression in response to Pgc-1 alpha. The present results indicate that Pgc-1 alpha controls Sirt3 gene expression and this action is an essential component of the overall mechanisms by which Pgc-1 alpha induces the full acquisition of a brown adipocyte differentiated phenotype.