Transcriptional Regulation of Fat Metabolism by PPARgamm

过氧化物酶体增殖物激活受体-γ（PPARgamma）和-δ（PPARdelta）是脂肪代谢的主要调节剂。它们属于配体激活转录因子的核受体超家族。高度选择性的PPARgamma和PPARdelta配体是用于治疗2型糖尿病和肥胖症的有前景的药物或药物候选物。然而，这些配体作为抗糖尿病和/或抗肥胖剂的分子机制在很大程度上仍然不清楚。核受体生物学的三方性质表明，配体的生物学效应是由这三个部分之间的组合协作决定的：配体，核受体和辅因子（辅激活子或辅抑制子）由靶基因启动子上的配体结合的核受体募集。为了了解配体激活的PPARgamma和PPARdelta转录调节脂肪代谢的分子机制，已经启动了三个使用蛋白质组学和基因组学方法的项目： I：分离和表征调节PPARgamma转录活性的组蛋白甲基转移酶复合物。 II：PPARdelta转录辅因子的分离和表征。

Peroxisome proliferator-activated receptor-gamma (PPARgamma) and -delta (PPARdelta) are major regulators of fat metabolism. They belong to the nuclear receptor super-family of ligand activated transcription factors. Highly selective PPARgamma and PPARdelta ligands are promising drugs or drug candidates for the treatment of type 2 diabetes and obesity. However, the molecular mechanism by which these ligands act as anti-diabetes and/or anti-obesity agents has largely remained unclear. The tripartite nature of the nuclear receptor biology suggests that the biological effect of a ligand is determined by the combinatorial collaboration among these three parts: ligand, nuclear receptor, and cofactors (coactivators or corepressors) recruited by ligand-bound nuclear receptor on the target gene promoters. To understand the molecular mechanism by which ligand-activated PPARgamma and PPARdelta transcriptionally regulate fat metabolism, three projects using proteomic and genomic approaches have been initiated: I: Isolation and characterization of a histone methyltransferase complex that regulates PPARgamma transcriptional activity. II: Isolation and characterization of transcription cofactors for PPARdelta.