Feed-Forward Inhibition of Androgen Receptor Activity by Glucocorticoid Action in Human Adipocytes
Feed-Forward Inhibition of Androgen Receptor Activity by Glucocorticoid Action in Human Adipocytes
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DOI：
10.1016/j.chembiol.2012.07.020
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发表时间：
2012-09-21
影响因子：
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通讯作者：
Mancini, Michael A.
中科院分区：
文献类型：
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作者：
Hartig, Sean M.;He, Bin;Mancini, Michael A.
我们比较了终末分化的小鼠3 T3-L1和人脂肪细胞的转录组，以确定细胞特异性差异。基因表达和高含量分析（HCA）的数据确定了雄激素受体（AR）的表达和功能，专门在早期人类脂肪细胞分化。AR激动剂二氢睾酮（DHT）通过下调脂肪细胞标志物基因来抑制人类脂肪细胞成熟，但在3 T3-L1中则不然。有趣的是，AR诱导与糖皮质激素受体（GR）的地塞米松激活相对应;然而，当暴露于脂肪细胞成熟所需的分化鸡尾酒时，AR采用拮抗剂构象并被转录抑制。为了进一步探索鸡尾酒中的效应物，我们应用基于图像的支持向量机（SVM）分类方案来显示脂肪细胞分化组分抑制AR作用。结果表明，人脂肪细胞分化，通过GR激活，上调AR，但也抑制AR转录活性。
We compared transcriptomes of terminally differentiated mouse 3T3-L1 and human adipocytes to identify cell-specific differences. Gene expression and high content analysis (HCA) data identified the androgen receptor (AR) as both expressed and functional, exclusively during early human adipocyte differentiation. The AR agonist dihydrotestosterone (DHT) inhibited human adipocyte maturation by downregu-lation of adipocyte marker genes, but not in 3T3-L1. It is interesting that AR induction corresponded with dexamethasone activation of the glucocorticoid receptor (GR); however, when exposed to the differentiation cocktail required for adipocyte maturation, AR adopted an antagonist conformation and was transcriptionally repressed. To further explore effectors within the cocktail, we applied an image-based support vector machine (SVM) classification scheme to show that adipocyte differentiation components inhibit AR action. The results demonstrate human adipocyte differentiation, via GR activation, upregu-lates AR but also inhibits AR transcriptional activity.