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首页> 外文期刊>Endocrinology >Inactivation of Histone Deacetylase 1 (HDAC1) But Not HDAC2 Is Required for the Glucocorticoid-Dependent CCAAT/Enhancer-Binding Protein alpha (C/EBP alpha) Expression and Preadipocyte Differentiation
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Inactivation of Histone Deacetylase 1 (HDAC1) But Not HDAC2 Is Required for the Glucocorticoid-Dependent CCAAT/Enhancer-Binding Protein alpha (C/EBP alpha) Expression and Preadipocyte Differentiation

机译：组蛋白去乙酰化酶1（HDAC1）灭活，但糖皮质激素依赖性CCAAT /增强子结合蛋白alpha（C / EBP alpha）表达和前脂肪细胞分化不需要HDAC2

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摘要

Several drugs currently used in the management of mood disorders, epilepsy (ie, valproic acid), or the control of inflammation (ie, corticosteroids) have been shown to promote visceral obesity in humans by increasing the number of newly formed adipocytes. Valproic acid is classified as a nonspecific histone deacetylase (HDAC) inhibitor, along with trichostatin A and butyric acid. In vitro experiments have demonstrated that such molecules greatly enhance the rate of preadipocyte differentiation, similarly to the effect of corticosteroids. The glucocorticoid receptor stimulates adipogenesis in part by enhancing the transcription of C/ebpa through the titration, and subsequent degradation, of HDAC1 from the C/ebp alpha promoter. There is, however, controversy in the literature as to the role of HDACs during adipogenesis. In this study, we sought to demonstrate, using 2 different strategies, the definite role of HDAC1 in adipogenesis. By using small interference RNA-mediated knockdown of HDAC1 and by generating an enzymatically inactive HDAC1(D181A) by site-directed mutagenesis, we were able to show that HDAC1, but not HDAC2, suppresses glucocorticoid receptor-potentiated preadipocyte differentiation by decreasing CCAAT/enhancer-binding protein (C/ebp)alpha and Ppar gamma expression levels at the onset of differentiation. Finally, we demonstrate that HDAC1(D181A) acts as adominant negative mutant of HDAC1 during adipogenesis by modulating C/EBP alpha transcriptional activity on the C/ebp alpha promoter.
机译：目前已显示出几种用于情绪障碍，癫痫（即丙戊酸）或炎症控制（即皮质类固醇）的药物可通过增加新形成的脂肪细胞数量来促进人类内脏肥胖。丙戊酸与曲古抑菌素A和丁酸一起被列为非特异性组蛋白脱乙酰基酶（HDAC）抑制剂。体外实验表明，此类分子极大地提高了前脂肪细胞分化的速率，类似于皮质类固醇的作用。糖皮质激素受体部分地通过从C / ebp alpha启动子滴定HDAC1并随后降解HDAC1来增强C / ebpa的转录，从而刺激脂肪生成。然而，文献中关于HDAC在脂肪形成过程中的作用存在争议。在这项研究中，我们试图证明使用两种不同的策略，HDAC1在脂肪形成中的明确作用。通过使用小干扰RNA介导的HDAC1敲低并通过定点诱变产生酶活性HDAC1（D181A），我们能够证明HDAC1（而非HDAC2）通过降低CCAAT /增强子抑制糖皮质激素受体增强的前脂肪细胞分化分化开始时结合蛋白（C / ebp）α和Pparγ的表达水平。最后，我们证明了HDAC1（D181A）在脂肪形成过程中通过调节C / ebp alpha启动子上的C / EBP alpha转录活性而充当HDAC1的主要阴性突变体。

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