Pennington Biomedical Research Center, 6400 Perkins Road, Baton Rouge, Louisiana 70808, USA.
Endocrinology. 2012 Mar;153(3):1206-18. doi: 10.1210/en.2011-1725. Epub 2012 Jan 31.
Moderate reductions in peroxisome proliferator-activated receptor (PPAR)γ levels control insulin sensitivity as effectively as activation of PPARγ in adipocytes by the thiazolidinediones. That observation suggests that PPARγ activity can be regulated by modulating the amount of PPARγ protein in adipocytes. Activation of PPARγ in adipocytes is linked to changes in PPARγ protein levels via increased degradation of PPARγ proteins by the ubiquitin proteasome system. Identification of the ubiquitin ligase or ligases that recognize ligand bound PPARγ is an essential step in determining the physiological significance of the relationship between activation and ubiquitin-dependent degradation of PPARγ. Using an RNA interference-based screen, we identified five RING (really interesting new gene)-type ubiquitin ligases that alter PPARγ protein levels in adipocytes. Here, we demonstrate that Drosophila seven-in-absentia homolog 2 (Siah2), a mammalian homolog of Drosophila seven-in-absentia, regulates PPARγ ubiquitylation and ligand-dependent activation of PPARγ in adipocytes. We also demonstrate that Siah2 expression is up-regulated during adipogenesis and that PPARγ interacts with Siah2 during adipogenesis. In addition, Siah2 is required for adipogenesis. These data suggest that modulation of PPARγ protein levels by the ubiquitin ligase Siah2 is essential in determining the physiological effects of PPARγ activation in adipocytes.
中等程度降低过氧化物酶体增殖物激活受体 (PPAR)γ 水平能像噻唑烷二酮激活脂肪细胞中的 PPARγ 一样有效地控制胰岛素敏感性。这一观察结果表明，PPARγ 活性可以通过调节脂肪细胞中 PPARγ 蛋白的数量来调节。脂肪细胞中 PPARγ 的激活与 PPARγ 蛋白水平的变化有关，这是通过泛素蛋白酶体系统增加 PPARγ 蛋白的降解来实现的。鉴定识别配体结合的 PPARγ 的泛素连接酶或连接酶是确定激活和 PPARγ 泛素依赖性降解之间关系的生理意义的关键步骤。我们使用基于 RNA 干扰的筛选方法，鉴定了五种 RING（真正有趣的新基因）型泛素连接酶，它们能改变脂肪细胞中的 PPARγ 蛋白水平。在这里，我们证明果蝇缺失基因 7 同源物 2（Siah2），即果蝇缺失基因 7 的哺乳动物同源物，调节脂肪细胞中 PPARγ 的泛素化和配体依赖性激活。我们还证明了 Siah2 在脂肪生成过程中表达上调，并且在脂肪生成过程中 PPARγ 与 Siah2 相互作用。此外，Siah2 是脂肪生成所必需的。这些数据表明，泛素连接酶 Siah2 对 PPARγ 蛋白水平的调节对于确定脂肪细胞中 PPARγ 激活的生理效应至关重要。
