Dlx5 Represses the Transcriptional Activity of PPARγ
Dlx5 Represses the Transcriptional Activity of PPARγ
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DOI：
10.1248/bpb.b21-00245
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发表时间：
2021-09-01
影响因子：
2
通讯作者：
Lee, Kwang Youl
中科院分区：
文献类型：
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作者：
Kim, Chae Yul;Cho, Dong Hyeok;Lee, Kwang Youl
过氧化物酶体增殖物激活受体γ（PPARgamma）是脂肪细胞分化中的主要转录因子，而无远端同源框5（Dlx 5）通过驱动Runt相关转录因子2表达而对启动成骨细胞分化至关重要。考虑到脂肪细胞和成骨细胞共享共同的祖细胞，骨和脂肪形成之间存在相互关系。然而，Dlx 5控制PPAR γ的机制仍不清楚。我们阐明了Dlx 5在免疫沉淀过程中对PPAR γ的物理阻碍;特别是，PPAR γ的配体结合和DNA结合结构域参与了相互作用。过氧化物酶体增殖物激活受体γ的转录活性显着降低Dlx 5过表达，而相反的结果与Dlx 5敲低检测。罗格列酮，一种过氧化物酶体增殖物激活受体γ激动剂，进一步增强了过氧化物酶体增殖物激活受体γ诱导的转录活性;然而，Dlx 5过表达有效地抑制了罗格列酮介导的活性增加。最后，DNA结合亲和力测定显示，Dlx 5中断了PPAR γ与PPAR γ反应元件启动子的相互作用。总之，我们的研究结果表明，Dlx 5阻碍了PPAR γ诱导的活性，它可能是有用的管理糖尿病药物介导的肥胖。
Peroxisome proliferator-activated receptor gamma (PPAR gamma) is a master transcription factor in adipocyte differentiation, while distal-less homeobox 5 (Dlx5) is essential for initiating osteoblast differentiation by driving Runt-related transcription factor 2 expression. Considering that adipocytes and osteoblasts share common progenitors, there is a reciprocal correlation between bone and fat formation. However, the mechanism by which Dlx5 controls PPAR gamma remains unclear. We elucidated that Dlx5 physically hinds to PPAR gamma during immunoprecipitation; in particular, the ligand-binding and DNA-binding domains of PPAR gamma were involved in the interaction. Transcriptional activity of PPAR gamma was significantly decreased by Dlx5 overexpression, whereas the opposite results were detected with Dlx5 knockdown. Rosiglitazone, a PPAR gamma agonist, further enhanced the PPAR gamma-induced transcriptional activity; however, Dlx5 overexpression effectively repressed the rosiglitazone-mediated increase in activity. Finally, DNA-binding affinity assay revealed that Dlx5 interrupts the interaction of PPAR gamma with the PPAR gamma response element promoter. In conclusion, our findings indicate that Dlx5 impedes PPAR gamma-induced activity, and it may be useful for managing diabetes drugmediated obesity.