Anti-Inflammatory, Antioxidant, and WAT/BAT-Conversion Stimulation Induced by Novel PPAR Ligands: Results from Ex Vivo and In Vitro Studies.

Activation of peroxisome proliferator-activated receptors (PPARs) not only regulates multiple metabolic pathways, but mediates various biological effects related to inflammation and oxidative stress. We investigated the effects of four new PPAR ligands containing a fibrate scaffold-the PPAR agonists ( (αEC 1.0 μM) and (γEC 0.012 μM)) and antagonists ( (αIC 6.5 μM) and (αIC 0.98 μM, with a weak antagonist activity on γ isoform))-on proinflammatory and oxidative stress biomarkers. The PPAR ligands and (0.1-10 μM) were tested on isolated liver specimens treated with lipopolysaccharide (LPS), and the levels of lactate dehydrogenase (LDH), prostaglandin (PG) E, and 8-iso-PGFα were measured. The effects of these compounds on the gene expression of the adipose tissue markers of browning, PPARα, and PPARγ, in white adipocytes, were evaluated as well. We found a significant reduction in LPS-induced LDH, PGE, and 8-iso-PGFα levels after treatment. On the other hand, decreased LPS-induced LDH activity. Compared to the control, stimulated uncoupling protein 1 (UCP1), PR-(PRD1-BF1-RIZ1 homologous) domain containing 16 (PRDM16), deiodinase type II (DIO2), and PPARα and PPARγ gene expression, in 3T3-L1 cells. Similarly, increased UCP1, DIO2, and PPARγ gene expression. caused a reduction in the gene expression of UCP1, PRDM16, and DIO2 when tested at 10 μM. In addition, significantly decreased PPARα gene expression. A significant reduction in PPARγ gene expression was also found after treatment. The novel PPARα agonist might be a promising lead compound and represents a valuable pharmacological tool for further assessment. The PPARγ agonist could play a minor role in the regulation of inflammatory pathways.