Please use this identifier to cite or link to this item: https://biore.bio.bg.ac.rs/handle/123456789/6437
Title: Mechanisms of peroxisome proliferator activated receptor γ regulation by non-steroidal anti-inflammatory drugs
Authors: Puhl, Ana
Milton, Flora
Čvoro, Aleksandra 
Douglas H Sieglaff,
Lois de Oliveira Campos, Jéssica
Bernardes, Amanda
Filgueira, Carly
Lammel Lindemann, Jan Antonio
Deng, Tuo
Neves, Francisco A. R.
Polikarpov, Igor
Webb, Paul
Keywords: Non-steroidal anti-inflammatory drugs;;Peroxisome proliferator activated receptors;;X-ray structure;;Gene expression;;3T3-L1;;Partial agonist.
Issue Date: Oct-2015
Publisher: Nuclear Receptor Signaling Atlas
Journal: Nuclear Receptor Signaling
Volume: 13
Issue: 1
Start page: e004
Abstract: 
Non-steroidal anti-inflammatory drugs (NSAIDs) display anti-inflammatory, antipyretic and analgesic properties by inhibiting cyclooxygenases and blocking prostaglandin production. Previous studies, however, suggested that some NSAIDs also modulate peroxisome proliferator activated receptors (PPARs), raising the possibility that such off target effects contribute to the spectrum of clinically relevant NSAID actions. In this study, we set out to understand how peroxisome proliferator activated receptor-γ (PPARγ/PPARG) interacts with NSAIDs using X-ray crystallography and to relate ligand binding modes to effects on receptor activity. We find that several NSAIDs (sulindac sulfide, diclofenac, indomethacin and ibuprofen) bind PPARγ and modulate PPARγ activity at pharmacologically relevant concentrations. Diclofenac acts as a partial agonist and binds to the PPARγ ligand binding pocket (LBP) in typical partial agonist mode, near the β-sheets and helix 3. By contrast, two copies of indomethacin and sulindac sulfide bind the LBP and, in aggregate, these ligands engage in LBP contacts that resemble agonists. Accordingly, both compounds, and ibuprofen, act as strong partial agonists. Assessment of NSAID activities in PPARγ-dependent 3T3-L1 cells reveals that NSAIDs display adipogenic activities and exclusively regulate PPARγ-dependent target genes in a manner that is consistent with their observed binding modes. Further, PPARγ knockdown eliminates indomethacin activities at selected endogenous genes, confirming receptor-dependence of observed effects. We propose that it is important to consider how individual NSAIDs interact with PPARγ to understand their activities, and that it will be interesting to determine whether high dose NSAID therapies result in PPAR activation.
URI: https://biore.bio.bg.ac.rs/handle/123456789/6437
DOI: 10.1621/nrs.13004
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