Minireview: Challenges and opportunities in development of PPAR agonists

Abstract

The clinical impact of the fibrate and thiazolidinedione drugs on dyslipidemia and diabetes is driven mainly through activation of two transcription factors, peroxisome proliferator-activated receptors (PPAR)-α and PPAR-γ. However, substantial differences exist in the therapeutic and side-effect profiles of specific drugs. This has been attributed primarily to the complexity of drug-target complexes that involve many coregulatory proteins in the context of specific target gene promoters. Recent data have revealed that some PPAR ligands interact with other non-PPAR targets. Here we review concepts used to develop new agents that preferentially modulate transcriptional complex assembly, target more than one PPAR receptor simultaneously, or act as partial agonists. We highlight newly described on-target mechanisms of PPAR regulation including phosphorylation and nongenomic regulation. We briefly describe the recently discovered non-PPAR protein targets of thiazolidinediones, mitoNEET, and mTOT. Finally, we summarize the contributions of on- and off-target actions to select therapeutic and side effects of PPAR ligands including insulin sensitivity, cardiovascular actions, inflammation, and carcinogenicity.

Figure 1.. Tissue-specific actions of PPARs.

Apo, apolipoprotein; HDL, high-density lipoprotein; VLDL, very low-density lipoprotein.

Figure 2.. A, Role of cofactors in PPAR function. In the unliganded state, corepressor proteins such as NCoR/silencing mediator of retinoid and thyroid receptors (SMRT) inhibit transcription by interacting with histone deacetylases. B, Upon binding of a ligand to the PPAR, the receptor undergoes a conformational change, NCoR/SMRT and histone deacetylases (HDACs) dissociate, and transcriptional coactivators such as PGC1-a or SRC-1 are recruited along with histone acetyltransferases (HAT), which open chromatin to allow interaction with RNA polymerase II. C, Each ligand may induce slightly different conformations of the receptor that influence the recruitment of coactivators and may lead to overlapping but unique transcriptional profiles in different cells and tissues. ♣, Unique genes regulated by each ligand; ♠, common target genes.

Figure 3.. Mitochondrial targets of thiazolidinediones.

A, MitoNeet. MitoNEET is an integral iron-sulfur (FeS)-containing protein in the outer mitochondrial membrane and regulates mitochondrial respiratory rates [adapted from Kusminski et al (68)]. B, MPC/mTOT. After glycolysis in the cytosol, pyruvate diffuses through the outer mitochondrial membrane and is then transported by the mitochondrial pyruvate carrier, MPC/mTOT, across the inner mitochondrial membrane. In the matrix, pyruvate is oxidized to produce ATP, supporting the processes of gluconeogenesis and lipogenesis. Both proteins have been shown to be non-PPAR targets of the thiazolidinedione class of diabetes agents. Acetyl CoA, acetyl–coenzyme A.