Abstract
Thiazolidinediones (TZDs) act through peroxisome proliferator activated receptor (PPAR) γ to increase insulin sensitivity in type 2 diabetes (T2DM), but deleterious effects of these ligands mean that selective modulators with improved clinical profiles are needed. We obtained a crystal structure of PPARγ ligand binding domain (LBD) and found that the ligand binding pocket (LBP) is occupied by bacterial medium chain fatty acids (MCFAs). We verified that MCFAs (C8–C10) bind the PPARγ LBD in vitro and showed that they are low-potency partial agonists that display assay-specific actions relative to TZDs; they act as very weak partial agonists in transfections with PPARγ LBD, stronger partial agonists with full length PPARγ and exhibit full blockade of PPARγ phosphorylation by cyclin-dependent kinase 5 (cdk5), linked to reversal of adipose tissue insulin resistance. MCFAs that bind PPARγ also antagonize TZD-dependent adipogenesis in vitro. X-ray structure B-factor analysis and molecular dynamics (MD) simulations suggest that MCFAs weakly stabilize C-terminal activation helix (H) 12 relative to TZDs and this effect is highly dependent on chain length. By contrast, MCFAs preferentially stabilize the H2-H3/β-sheet region and the helix (H) 11-H12 loop relative to TZDs and we propose that MCFA assay-specific actions are linked to their unique binding mode and suggest that it may be possible to identify selective PPARγ modulators with useful clinical profiles among natural products.
Highlights
Peroxisome proliferator activated receptors (PPARs a, b/d and c) are ligand-dependent transcription factors that are prominent targets for pharmaceutical development
It is likely that our purification procedures did not strip medium chain fatty acids (MCFAs) from the PPARc preparations and the presence of these contaminating ligands increased peroxisome proliferator activated receptor (PPAR) stability and facilitated crystallization
Our studies indicate that C8–C10 MCFAs are PPARc partial agonists; this is in line with another study which shows that DA (C10) is a PPARc modulator [19]
Summary
Peroxisome proliferator activated receptors (PPARs a, b/d and c) are ligand-dependent transcription factors that are prominent targets for pharmaceutical development. Thiazolidinediones (TZDs) act through PPARc to elicit increased sensitivity to insulin in type 2 diabetes mellitus (T2DM) and reduce inflammation in arteries [1]. TZDs exhibit deleterious effects on fat accumulation, fluid retention and bone density and increase risk of heart failure, indicating a need for new selective PPARc ligands with improved clinical profiles [1,2,3]. At least some insulin sensitizing effects of TZDs mediated by PPARc do not require full agonist actions; TZDs block cyclindependent kinase 5 (Cdk 5) mediated phosphorylation of PPARc ser273, which reduces expression of key adipokines in fat cells [10]. Improved knowledge of relationships of PPARc ligand binding modes and relationships to partial agonism and secondary modifications could help us develop selective ligands that act as safer PPARc modulators
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