Lipin1 regulates PPARγ transcriptional activity.
Lipin1 regulates PPARγ transcriptional activity.
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DOI：
10.1042/bj20121598
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发表时间：
2013-07-01
期刊：
影响因子：
--
通讯作者：
Kim KS
中科院分区：
文献类型：
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作者：
Kim HE;Bae E;Jeong DY;Kim MJ;Jin WJ;Park SW;Han GS;Carman GM;Koh E;Kim KS
过氧化物酶体增殖物激活受体γ(Peroxisome Proplator-Actiated Receptor-γ，PPAR)是一种主要的转录因子，通过调节脂肪细胞特异性基因的表达参与脂肪的形成。最近，脂蛋白1被发现通过调节C/EBPα(CCAAT/增强子结合蛋白α)和PPARγ网络而成为脂肪细胞成熟和维持的关键因子，但其影响PPARγ转录活性的确切机制在很大程度上尚不清楚。本研究的结果表明，在缺乏配体罗格列酮的情况下，脂蛋白1通过从PPARγ中释放共抑制因子NCOR1(核受体共抑制因子1)和SMRT(维甲酸和甲状腺激素受体沉默介质)来激活PPARγ。我们还在第217和399残基之间发现了一个新的脂蛋白1 TAD(转录激活结构域)，它对PPARγ的激活是关键的，但对PPARα的激活没有关键作用。此外，该TAD是Lipin1所特有的，因为该区域与其他Lipin亚型，Lipin2和Lipin3没有任何同源性。P300和sRC-1(类固醇受体共激活剂1)可增强脂蛋白1TAD的活性，而pCAF(p300/CBP相关因子)和pGC-1α(PPAR共激活剂1α)则不能增强其活性。Lipin1与PPARγ的物理相互作用发生在Lipin1的第82 5~92 6位C末端区域，第885位的VXXL1基序是与PPARγ结合和激活的关键。脂蛋白1作为PPARγ共激活剂促进脂肪细胞分化，TAD和VXXL1基序起关键作用，但与脂蛋白1的催化活性无直接关系。综上所述，这些数据表明，Lipin1通过其释放共抑制物和招募共激活子的能力，而不是通过PPARγ激活的机制来发挥PPARα活性的关键调节作用。
PPARγ (peroxisome proliferator-activated receptor-γ) is a master transcription factor involved in adipogenesis through regulating adipocyte-specific gene expression. Recently, lipin1 was found to act as a key factor for adipocyte maturation and maintenance by modulating the C/EBPα (CCAAT/enhancer-binding protein α) and PPARγ network; however, the precise mechanism by which lipin1 affects the transcriptional activity of PPARγ is largely unknown. The results of the present study show that lipin1 activates PPARγ by releasing co-repressors, NcoR1 (nuclear receptor co-repressor 1) and SMRT (silencing mediator of retinoid and thyroid hormone receptor), from PPARγ in the absence of the ligand rosiglitazone. We also identified a novel lipin1 TAD (transcriptional activation domain), between residues 217 and 399, which is critical for the activation of PPARγ, but not PPARα. Furthermore, this TAD is unique to lipin1 since this region does not show any homology with the other lipin isoforms, lipin2 and lipin3. The activity of the lipin1 TAD is enhanced by p300 and SRC-1 (steroid receptor co-activator 1), but not by PCAF (p300/CBP-associated factor) and PGC-1α (PPAR co-activator 1α). The physical interaction between lipin1 and PPARγ occurs at the lipin1 C-terminal region from residues 825 to 926, and the VXXLL motif at residue 885 is critical for binding with and the activation of PPARγ. The action of lipin1 as a co-activator of PPARγ enhanced adipocyte differentiation; the TAD and VXXLL motif played critical roles, but the catalytic activity of lipin1 was not directly involved. Collectively, these data suggest that lipin1 functions as a key regulator of PPARγ activity through its ability to release co-repressors and recruit co-activators via a mechanism other than PPARα activation.