Class II Histone Deacetylases Limit GLUT4 Gene Expression during Adipocyte Differentiation
Class II Histone Deacetylases Limit GLUT4 Gene Expression during Adipocyte Differentiation
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DOI：
10.1074/jbc.m110.157107
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发表时间：
2011-01-07
影响因子：
4.8
通讯作者：
Olson, Ann Louise
中科院分区：
文献类型：
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作者：
Weems, Juston;Olson, Ann Louise
胰岛素依赖性葡萄糖稳态对脂肪细胞中胰岛素响应性葡萄糖转运蛋白4（GLUT 4）表达水平高度敏感。GLUT 4蛋白表达水平高度依赖于GLUT 4基因转录速率。在胰岛素抵抗的各种生理状态下，包括2型糖尿病、肥胖和长期禁食，GLUT 4基因转录都会减少。GLUT 4基因在脂肪细胞中的表达是分化依赖性的，完全表达延迟到分化程序的后期。在本文中，我们已经测试了这一假设，即在3 T3-L1脂肪细胞中的分化依赖性GLUT 4基因表达依赖于核浓度的II类组蛋白脱乙酰酶（HDAC）蛋白，HDAC 5。我们已经通过使用两种实验方法降低3 T3-L1前脂肪细胞核室中II类HDAC的水平来测试这一假设。首先，前脂肪细胞用苯肾上腺素（一种α-肾上腺素能受体激动剂）处理，以将HDACS赶出核室。此外，使用siRNA敲低降低II类HDAC浓度。在每种情况下，减少核II类HDAC浓度导致内源性GLUT 4 mRNA在前脂肪细胞中的表达增加。总之，我们的数据表明，II类HDAC表达是抑制GLUT 4表达的主要调控机制在分化前状态。
Insulin-dependent glucose homeostasis is highly sensitive to the levels of insulin-responsive glucose transporter 4 (GLUT4) expression in adipocytes. The level of GLUT4 protein expression is highly dependent on the rate of GLUT4 gene transcription. GLUT4 gene transcription is decreased in a variety of physiologic states of insulin resistance including type 2 diabetes, obesity, and prolonged fasting. GLUT4 gene expression in adipocytes is differentiation-dependent, with full expression delayed until late in the differentiation program. In this paper, we have tested the hypothesis that differentiation-dependent GLUT4 gene expression in 3T3-L1 adipocytes is dependent on the nuclear concentration of a class II histone deacetylase (HDAC) protein, HDAC5. We have tested this hypothesis by reducing the levels of class II HDACs in the nuclear compartment of 3T3-L1 preadipocytes using two experimental approaches. First, preadipocytes were treated with phenylephrine, an alpha-adrenergic receptor agonist, to drive HDACS out of the nuclear compartment. Also, the class II HDAC concentrations were reduced using siRNA knockdown. In each case, reduction of nuclear class II HDAC concentration resulted in increased expression of endogenous GLUT4 mRNA in preadipocytes. Together, our data indicate that class II HDAC expression is the major regulatory mechanism for inhibiting GLUT4 expression in the predifferentiated state.