Peroxisome Proliferator-activated Receptor Assays

Background of Peroxisome Proliferator-activated Receptor (PPAR)

PPAR, a nuclear receptor, is widely distributed in various tissues throughout the body. It is well known that the PPAR family contains three isoforms: PPARα, PPARδ, and PPARγ. These isoforms differ from each other in ligand specificity, tissue location, and physiological effect. Each of them targets various genes. All subtypes are implicated in controlling the energy balance as well as regulating the activities of the immune cells.

Fig.1 Tridimensional structure of LBD for PPARs. Fig.1. Tridimensional structure of LBD for PPARs. (Pirat, 2012)

Roles of PPARs

PPARα is predominantly found in metabolically active regions, such as adipose tissue. Moreover, PPARα is also present in the liver, large intestine, and skeletal muscle. PPARα is an essential component for the regulation of lipid metabolism. Notably, PPARγ is the most extensively studied of the three receptors, Additionally, PPARγ is a critical regulator of the cell cycle, cell differentiation, and adipogenesis. PPARδ is ubiquitously expressed in a variety of tissues. Studies have provided evidence that PPARδ is closely related to fatty acid catabolism and energy metabolism.

Mechanisms of PPARs

PPARs mediate diverse functions by participating in multiple pathways.

Receptor	Gene	Mechanism	Agonists	Antagonists
PPARα	PPARA	PPARα induces cholesterol efflux from foam cells through activation of the LXR-ABCA1 pathway.	CP 775146 Fenofibrate GW 7647 Oleylethanolamide WY 14643	GW 6471 MK 886
PPARβ	PPARD	The anti-inflammatory effect of PPARδ is mediated by the TAK-1-NF-κB pathway.	GW 0742 GW 501516 L-165,041	FH 535 GSK 0660 GSK 3787
PPARγ	PPARG	PPARγ signals via MAP kinase and NF-kB pathways.	Ciglitazone Edaglitazone nTZDpa Rosiglitazone Telmisartan Troglitazone	FH 535 GW 9662 SR 16832 SR 202 T 0070907

Published Data

Paper Title	Peroxisome Proliferator-Activated Receptors and the Hallmarks of Cancer
Journal	Cells
Published	2022
Abstract	PPARs function as nuclear transcription factors following physiological or pharmacological ligand binding and heterodimerization with the retinoic acid X receptor. Physiological ligands comprise fatty acids and fatty acid-derived compounds with low specificity for diverse PPAR isoforms. For each PPAR subtype, specific pharmacological agonists and antagonists, as well as pan-agonists, are available. Consistent with its natural ligands, PPARs are critical targets for the therapy of metabolic syndrome as well as its related complications. In addition, many lines of evidence suggest that PPARs are closely associated with malignancies. To better assess the important role of PPAR modulators in the treatment of malignancies in personalized medicine, it is necessary to summarize the three PPARs associated with cancer hallmark capabilities. This article describes the function of PPAR beta/delta as a hallmark of cancer and the impact of PPAR in angiogenesis.
Result	Determining the effect of a particular agonist or antagonist on cancer therapy is difficult due to the many various functions of PPARs in cancer markers. Different cancer types and each cancer type affects stromal and tumor cells differently. It is worth noting that the exploration of dual and pan-PPAR modulators is beneficial for the development of new therapeutic strategies. Fig.2. Summary of the effects of PPARα, PPARβ/δ, and PPARγ on tumor metabolism. (Wagner, 2022)

References

Pirat, C.; et al. Targeting peroxisome proliferator-activated receptors (PPARs): development of modulators. Journal of medicinal chemistry. 2012; 55(9): 4027-4061.
Wagner, N.; Wagner, K.D. Peroxisome Proliferator-Activated Receptors and the Hallmarks of Cancer. Cells. 2022; 11(15): 2432.

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