Regulation of adipogenesis by nuclear receptor PPARγ is modulated by the histone demethylase JMJD2C.
Regulation of adipogenesis by nuclear receptor PPARγ is modulated by the histone demethylase JMJD2C.
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DOI：
10.1590/s1415-47572010005000105
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发表时间：
2011-01
影响因子：
2.1
通讯作者：
Vargas D
中科院分区：
文献类型：
--
作者：
Lizcano F;Romero C;Vargas D
对抗肥胖及其相关并发症的潜在策略包括修饰脂肪细胞中的基因表达以减少脂质积累。核受体过氧化物酶体激活受体γ（PPARγ）是脂肪细胞分化的主要调节因子，其功能激活目前被用作2型糖尿病的治疗方法。然而，PPARγ的完全激活诱导了可能由部分激活引起的不良继发性效应。一组产生组蛋白去甲基化的蛋白质已被证明可以改变核受体的转录活性。在这里，我们描述了jumonji结构域包含2C/赖氨酸脱甲基酶4C（JMJD 2C/KDM 4C）对PPARγ转录激活的抑制作用。JMJD 2C显著降低罗格列酮刺激的PPARγ活化。这种效应主要在使用Tudor结构域进行的实验中观察到，Tudor结构域可能与组蛋白去乙酰化酶1类（HDAC）相互作用，这种相互作用可能减少了介导的PPARγ激活。曲古抑菌素A是一种HDAC抑制剂，可降低JMJD 2C的抑制作用。当JMJD 2C在3 T3-L1细胞中过表达时，观察到Tudor结构域的分化减少。总之，我们在此描述了JMJD 2C介导的PPARgamma转录激活以及前脂肪细胞分化的减少。JMJD 2C的这种新作用可能在治疗肥胖及其并发症的新治疗方法中发挥重要作用。
A potential strategy to combat obesity and its associated complications involves modifying gene expression in adipose cells to reduce lipid accumulation. The nuclear receptor Peroxisome Proliferator-activated receptor gamma (PPARγ) is the master regulator of adipose cell differentiation and its functional activation is currently used as a therapeutic approach for Diabetes Mellitus type 2. However, total activation of PPARγ induces undesirable secondary effects that might be set with a partial activation. A group of proteins that produce histone demethylation has been shown to modify the transcriptional activity of nuclear receptors. Here we describe the repressive action of the jumonji domain containing 2C/lysine demethylase 4 C (JMJD2C/KDM4C) on PPARγ transcriptional activation. JMJD2C significantly reduced the rosiglitazone stimulated PPARγ activation. This effect was mainly observed in experiments performed using the Tudor domains that may interact with histone deacetylase class 1 (HDAC) and this interaction probably reduces the mediated activation of PPARγ. Trichostatin A, a HDAC inhibitor, reduces the repressive effect of JMJD2C. When JMJD2C was over-expressed in 3T3-L1 cells, a reduction of differentiation was observed with the Tudor domain. In summary, we herein describe JMJD2C-mediated reduction of PPARgamma transcriptional activation as well as preadipocyte differentiation. This novel action of JMJD2C might have an important role in new therapeutic approaches to treat obesity and its complications.