PPAR𝛾 Agonists: Potential as Therapeutics for Neovascular Retinopathies

Figure 3

Schematic diagram of the mechanisms of PPAR𝛾 action. In the unliganded state (top), the PPAR𝛾 receptor exists as a heterodimer with the RXR nuclear receptor and the heterodimer is located on a PPAR response element (PPRE) of a target gene. The unliganded receptor heterodimer complex is associated with a multicomponent corepressor complex, which physically interacts with the PPAR𝛾 receptor through silencing mediator for retinoid and thyroid hormone receptors (SMRT). The corepressor complex contains histone deacetylase (HDAC) activity, and the deacetylated state of histone inhibits transcription. After PPAR𝛾 ligand binding, the corepressor complex is dismissed, and a coactivator complex is recruited to the heterodimer PPAR𝛾 receptor (bottom). The coactivator complex contains histone acetylase activity, leading to chromatin remodeling, facilitating active transcription. (Adapted with permission from: J. M. Olefsky, “Treatment of insulin resistance with peroxisome proliferator-activated receptor gamma agonists.” Journal of Clinical Investigation, vol. 106, no. 4, pp. 467-472, 2000); C. K. Glass, M. G. Rosenfeld, “The coregulator exchange in transcriptional functions of nuclear receptors”. Genes & Development,vol. 14, no. 2, pp. 121-141, 2000.)