Transcriptional Regulation of Fat Metabolism by PPAR

过氧化物酶体增殖物激活受体-γ(PPARGamma)和-Delta(PPARDelta)是脂肪代谢的主要调节因子。它们属于核受体超家族配体激活的转录因子。高选择性的PPARGamma和PPARDelta配体是治疗2型糖尿病和肥胖症的有前途的药物或候选药物。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不清楚。核受体生物学的三部性表明，配体的生物学效应是由配体结合的核受体在靶基因启动子上募集的三个部分之间的组合协作决定的：配体、核受体和辅助因子(共激活或辅助抑制物)。为了了解配体激活的PPARGamma和PPARDelta转录调控脂肪代谢的分子机制，实验室与希望之城贝克曼研究所的Markus Kalkum博士合作，启动了三个使用蛋白质组和基因组方法的项目。 I：PPAR-γ转录辅因子的蛋白质组分离和鉴定。 II：PPARDelta转录辅因子的蛋白质组分离和鉴定。 III：PPARGamma和PPARDelta靶基因的鉴定和鉴定。

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 in the laboratory in collaboration with Dr. Markus Kalkum of the Beckman Research Institute of the City of Hope. I: Proteomic isolation and characterization of transcription cofactors for PPARgamma. II: Proteomic isolation and characterization of transcription cofactors for PPARdelta. III: Identification and characterization of PPARgamma and PPARdelta target genes.