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Flightless-1, a novel transcriptional modulator of PPAR gamma through competing with RXR alpha

机译：Flightless-1，一种与RXR alpha竞争的新型PPARγ转录调节剂

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摘要

Peroxisome proliferator-activated receptor gamma (PPAR gamma) is a member of the nuclear receptor family and plays key roles in glucose and lipid metabolism. Its transcriptional control of target genes is mediated by ligand-dependent recruitment of coactivators. In this study, we demonstrate that a novel transcriptional modulator of PPAR gamma, Flightless-I (FLII) binds directly to and suppresses the transcriptional activity of PPAR gamma. The LXXLL motif within the leucine-rich repeat (LRR) domain of FLII interacts directly with the DNA-binding domain of PPAR gamma. Interestingly, in the presence of PPAR gamma ligands, such as rosiglitazone and SR1664, this interaction was abolished in vitro. When FLII was overexpressed, both the transcriptional activity of PPAR gamma and adipogenesis were suppressed significantly, whereas specific knockdown of FLII reversed these effects. Furthermore, DNA occupancy of PPAR gamma on its target gene promoters was enhanced by FLII knockdown, and the interaction between PPAR gamma and retinoid X receptor alpha (RXR alpha) was blocked by FLII. Together, these findings strongly suggest that FLII functions in PPAR gamma activation as a molecular switch to repress transcriptional activity by interrupting formation of the PPAR gamma/RXR alpha complex, and FLII may serve as a novel therapeutic target in the treatment of adiposity-related metabolic syndromes. (C) 2014 Elsevier Inc. All rights reserved.
机译：过氧化物酶体增殖物激活受体γ（PPAR gamma）是核受体家族的成员，在葡萄糖和脂质代谢中起关键作用。它对靶基因的转录控制是由共激活剂的配体依赖性募集介导的。在这项研究中，我们证明了PPARγ的新型转录调节因子，Flightless-I（FLII）直接结合并抑制PPARγ的转录活性。 FLII的富含亮氨酸的重复（LRR）域中的LXXLL基序与PPARγ的DNA结合域直接相互作用。有趣的是，在存在PPARγ配体（如罗格列酮和SR1664）时，这种相互作用在体外被消除。当FLII过表达时，PPARγ的转录活性和脂肪形成均被显着抑制，而FLII的特异性敲低则逆转了这些作用。此外，通过FLII敲低可提高PPARγ在其靶基因启动子上的DNA占有率，并通过FLII阻止PPARγ与类维生素X受体α（RXRα）之间的相互作用。在一起，这些发现强烈表明，FLII通过中断PPAR gamma / RXRα复合物的形成，在PPARγ激活中起分子开关的作用，从而抑制转录活性，并且FLII可以作为治疗肥胖相关代谢的新型治疗靶标综合症。 （C）2014 Elsevier Inc.保留所有权利。

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