Dataset Information

PPAR? signaling and emerging opportunities for improved therapeutics.

ABSTRACT: Peroxisome proliferator-activated receptor gamma (PPAR?) is a ligand-activated nuclear receptor that regulates glucose and lipid metabolism, endothelial function and inflammation. Rosiglitazone (RGZ) and other thiazolidinedione (TZD) synthetic ligands of PPAR? are insulin sensitizers that have been used for the treatment of type 2 diabetes. However, undesirable side effects including weight gain, fluid retention, bone loss, congestive heart failure, and a possible increased risk of myocardial infarction and bladder cancer, have limited the use of TZDs. Therefore, there is a need to better understand PPAR? signaling and to develop safer and more effective PPAR?-directed therapeutics. In addition to PPAR? itself, many PPAR? ligands including TZDs bind to and activate G protein-coupled receptor 40 (GPR40), also known as free fatty acid receptor 1. GPR40 signaling activates stress kinase pathways that ultimately regulate downstream PPAR? responses. Recent studies in human endothelial cells have demonstrated that RGZ activation of GPR40 is essential to the optimal propagation of PPAR? genomic signaling. RGZ/GPR40/p38 MAPK signaling induces and activates PPAR? co-activator-1?, and recruits E1A binding protein p300 to the promoters of target genes, markedly enhancing PPAR?-dependent transcription. Therefore in endothelium, GPR40 and PPAR? function as an integrated signaling pathway. However, GPR40 can also activate ERK1/2, a proinflammatory kinase that directly phosphorylates and inactivates PPAR?. Thus the role of GPR40 in PPAR? signaling may have important implications for drug development. Ligands that strongly activate PPAR?, but do not bind to or activate GPR40 may be safer than currently approved PPAR? agonists. Alternatively, biased GPR40 agonists might be sought that activate both p38 MAPK and PPAR?, but not ERK1/2, avoiding its harmful effects on PPAR? signaling, insulin resistance and inflammation. Such next generation drugs might be useful in treating not only type 2 diabetes, but also diverse chronic and acute forms of vascular inflammation such as atherosclerosis and septic shock.

SUBMITTER: Wang S

PROVIDER: S-EPMC5026568 | biostudies-other | 2016 Sep

REPOSITORIES: biostudies-other

ACCESS DATA

Publications

PPARγ signaling and emerging opportunities for improved therapeutics.

Wang Shuibang S Dougherty Edward J EJ Danner Robert L RL

Pharmacological research 20160604

Peroxisome proliferator-activated receptor gamma (PPARγ) is a ligand-activated nuclear receptor that regulates glucose and lipid metabolism, endothelial function and inflammation. Rosiglitazone (RGZ) and other thiazolidinedione (TZD) synthetic ligands of PPARγ are insulin sensitizers that have been used for the treatment of type 2 diabetes. However, undesirable side effects including weight gain, fluid retention, bone loss, congestive heart failure, and a possible increased risk of myocardial in ...[more]

PMID: 27268145

Similar Datasets

Project description:IntroductionSupratentorial pediatric high-grade gliomas (pHGGs) are aggressive malignancies that lack effective treatment options. Deep genomic sequencing by multiple groups has revealed that the primary alterations unique to pHGGs occur in epigenetic and kinase genes. These mutations, fusions, and deletions present a therapeutic opportunity by use of small molecules targeting epigenetic modifiers and kinases that contribute to pHGG growth.MethodsUsing a targeted search of the pre-clinical literature and clinicaltrials.gov for kinase and epigenetic pathways in pHGG, we collectively describe how these mechanisms are being targeted in pre-clinical animal models and in current clinical trials, as well as propose unexplored therapeutic possibilities for future investigations.ResultsRelevant pHGG kinases are targetable by several FDA-approved or clinical-stage kinase inhibitors, including altered BRAF/MET/NTRK/ALK and wild-type PI3K/EGFR/PDGFR/VEGF/AXL. Epigenetic proteins implicated in pHGG are also clinically targetable and include histone erasers, writers and readers such as HDACs, demethylases LSD1/JMJD3, methyltransferase EZH2, chromatin reader bromodomains, and chromatin remodeler subunit BMI-1. Crosstalk between these pathways can occur involving kinases such as EGFR and AMPK interacting with epigenetic modifiers such as HDACs or EZH2. Single agent trial results of kinase inhibitors or epigenetic targets alone are underwhelming and hampered by poor pharmacokinetics, adaptive resistance, and broad inclusion criteria.ConclusionsThe genetic and phenotypic diversity of pHGGs is now well characterized after large-scale sequencing studies on patient tissue. However, clinical treatment paradigms have not yet shifted in response to this information. Combination therapies targeting multiple kinases or epigenetic targets may hold more promise, especially if attempted in selected patient populations with hemispheric pHGG tumors and relevant targeted therapeutic biomarkers.

Dataset Information

PPAR? signaling and emerging opportunities for improved therapeutics.

Publications

PPARγ signaling and emerging opportunities for improved therapeutics.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets