University of Hertfordshire

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Original languageEnglish
JournalJournal of Biological Chemistry
Publication statusSubmitted - 5 Jun 2020


Peroxisome proliferator activated receptor beta/delta (PPARβ/δ) is a nuclear receptor ubiquitously expressed in cells. PPARβ/δ signaling controls inflammation, lipid metabolism, glucose metabolism and insulin sensitivity, and has been considered a potential therapeutic target for these conditions. However, there are great discrepancies in the literature about the role of PPARβ/δ with both anti- and pro-effects on inflammation following ligand-activation of PPARβ/δ. Understanding the PPARβ/δ mode of action is of great interest and may provide new molecular mechanisms for treating a variety of inflammatory-related diseases. Here, we studied the PPARβ/δ-regulation of LPS-induced inflammation of three lung tissues from rat; pulmonary artery, bronchi and parenchyma, using different combinations of agonists (GW0742 or L-165402) and antagonists (GSK3787 or GSK0660). It was found that LPS-induced inflammation is largely regulated by PPARβ/δ in the pulmonary artery, but it is a minor regulation factor in bronchi or parenchyma. Incubation of the tissues with an agonist does not inhibit the inflammation but activates the PPARβ/δ induction mode of action. Surprisingly, the co-incubation of the tissue with agonist and antagonist shows anti-inflammatory effects and switches the PPARβ/δ mode of action from induction to trans-repression, indicating that the PPARβ/δ induction mode of action is pro-inflammatory and the trans-repression anti-inflammatory. The complexity of ligand binding is indicated through computational chemistry methods whereby the binding of PPARβ/δ agonists are predicted to form polar interactions with the residues His287, His413 and Tyr437 whilst PPARβ/δ antagonists form polar interactions with the residues Thr252 and Asn307. Further, our modelling indicates favourable binding energies and the feasibility of two ligands binding at same time into the PPARβ/δ binding pocket. In summary, this study provides novel insight into the complex relationship between ligand binding profiles and functional outcomes in a rat lung inflammation model, which will help inform the design of novel therapies for inflammatory lung diseases.

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