Tudor-SN, a Novel Coactivator of Peroxisome Proliferatoractivated Receptor γ Protein, Is Essential for Adipogenesis
Tudor-SN, a Novel Coactivator of Peroxisome Proliferatoractivated Receptor γ Protein, Is Essential for Adipogenesis
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Tudor-SN 是过氧化物酶体增殖物激活受体 γ 蛋白的新型共激活剂，对于脂肪生成至关重要
DOI：
10.1074/jbc.m113.523456
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发表时间：
2014-03-21
影响因子：
4.8
通讯作者：
Yang, Jie
中科院分区：
文献类型：
--
作者：
Duan, Zhongchao;Zhao, Xiujuan;Yang, Jie
背景：Tudor-SN 已在脂滴中观察到，但其在脂质稳态中的作用仍不清楚。结果：Tudor-SN和PPAR在脂肪形成过程中均受到C/EBP的调控，并显着影响PPAR靶基因的调控。结论：Tudor-SN 在脂肪生成中充当 PPAR 的共激活剂。意义：该研究阐明了调节脂肪生成的新功能机制。脂肪生成是间充质前体细胞分化为成熟脂肪细胞的过程，是一个精心策划的过程。在本研究中，我们确定 Tudor-SN 是转录因子过氧化物酶体增殖物激活受体 (PPAR) 的新型共激活剂。我们首次提供了 Tudor-SN 和 PPAR 存在于同一复合体中的证据。两者在脂肪形成过程中均被早期因子 C/EBP 上调，并在暴露于激素混合物后显着影响 3T3-L1 前脂肪细胞和小鼠胚胎成纤维细胞 (MEF) 中 PPAR 靶基因的调节。此外，aP2-PPAR反应元件（PPRE）与PPAR和Tudor-SN相互作用，并且PPRE-luc的基因转录激活通过Tudor-SN的异位表达而增强。 Tudor-SN 蛋白 (MEF-KO) 的缺失会影响但不会完全消除 PPAR 和 aP2-PPRE 的关联。功能丧失研究进一步证实Tudor-SN是脂肪生成所必需的，因为Tudor-SN（MEF-KO）的缺失会损害地塞米松、3-异丁基-1-甲基黄嘌呤和胰岛素（DMI）诱导的脂肪细胞分化以及PPAR靶基因（例如aP2和adipsin）的表达。此外，MEF-KO 中的 H3 乙酰化水平低于 MEF-WT。在 MEF-KO 中，HDAC1 和 HDAC3 均与 PPAR 稳定相关，而在 MEF-WT 中，在脂肪形成过程中治疗 5 天后，仅观察到少量关联。 PPAR需要多种共激活子或共阻遏物，它们可能动态关联并调节PPAR结合靶基因启动子区的高阶染色质重塑； Tudor-SN 可能是这些共激活剂之一。
Background: Tudor-SN has been observed in lipid droplets, but its role in lipid homeostasis remains unclear. Results: Tudor-SN and PPAR are both regulated by C/EBP during adipogenesis and significantly influence the regulation of PPAR target genes. Conclusion: Tudor-SN functions as a co-activator of PPAR in adipogenesis. Significance: The study has elucidated a new functional mechanism for the regulation of adipogenesis.Adipogenesis, in which mesenchymal precursor cells differentiate into mature adipocytes, is a well orchestrated process. In the present study we identified Tudor-SN as a novel co-activator of the transcription factor peroxisome proliferator-activated receptor (PPAR). We provide the first evidence that Tudor-SN and PPAR exist in the same complex. Both are up-regulated by the early factor C/EBP during adipogenesis and significantly influence the regulation of PPAR target genes in both 3T3-L1 pre-adipocyte and mouse embryonic fibroblasts (MEF) upon exposure to a mixture of hormonal mixture. Moreover, aP2-PPAR response element (PPRE) interacts with both PPAR and Tudor-SN, and the gene transcriptional activation of PPRE-luc is enhanced by ectopic expression of Tudor-SN. Deletion of Tudor-SN protein (MEF-KO) affects but does not completely abolish the association of PPAR and aP2-PPRE. Loss-of-function studies further verified that Tudor-SN is required for adipogenesis, as deletion of Tudor-SN (MEF-KO) impairs dexamethasone, 3-isobutyl-1-methylxanthine, and insulin (DMI)-induced adipocyte differentiation and the expression of PPAR target genes, such as aP2 and adipsin. Furthermore, H3 acetylation levels were lower in MEF-KO than MEF-WT. Both HDAC1 and HDAC3 are stably associated with PPAR in MEF-KO, whereas only a small amount of association was observed in MEF-WT after 5 days of treatment during adipogenesis. PPAR requires various co-activators or co-repressors, which may dynamically associate with and regulate the higher order chromatin remodeling of the promoter region of PPAR-bound target genes; Tudor-SN is likely one of these co-activators.