Peroxisome proliferator-activated receptor delta(PPAR-delta), or(PPAR-beta), also known asNuclear hormone receptor 1(NUC1) is anuclear receptor that in humans is encoded by thePPARDgene.[5]
PPAR-delta is anuclear hormone receptor that governs a variety of biological processes and may be involved in the development of several chronic diseases, including diabetes, obesity, atherosclerosis, and cancer.[7][8]
PPAR-delta may function as an integrator oftranscriptionrepression and nuclear receptor signaling. It activates transcription of a variety of target genes by binding to specific DNA elements. Well describedtarget genes of PPARδ includePDK4,ANGPTL4,PLIN2, andCD36. The expression of this gene is found to be elevated incolorectal cancer cells.[11] The elevated expression can be repressed by adenomatosis polyposis coli (APC), a tumor suppressor protein involved in the APC/beta-catenin signaling pathway. Knockout studies in mice suggested the role of this protein inmyelination of thecorpus callosum,epidermal cell proliferation, and glucose[12] and lipid metabolism.[13]
This protein has been shown to be involved in differentiation, lipid accumulation,[14] directional sensing, polarization, and migration inkeratinocytes.[15]
Studies into the role of PPAR-delta incancer have produced contradictory results. Although there is some controversy, the majority of studies have suggested that PPAR-delta activation could result in changes that are favorable to cancer progression.[16] PPAR-delta favours tumour angiogenesis.[17]
Knockout mice lacking the ligand binding domain of PPAR-delta are viable. However, these mice are smaller than the wild type bothneo andpostnatally. In addition, fat stores in thegonads of the mutants are smaller. The mutants also display increased epidermalhyperplasia upon induction withTPA.[19]
PPAR-delta is activated in the cell by variousfatty acids and fatty acid derivatives.[7] Examples of naturally occurring fatty acids that bind with and activate PPAR-delta includearachidonic acid and certain members of the15-hydroxyicosatetraenoic acid family of arachidonic acid metabolites including 15(S)-HETE, 15(R)-HETE, and 15-HpETE.[20] Several high affinity ligands for PPAR-delta have been developed, includingGW501516 andGW0742, which play an important role in research. In one study utilizing such a ligand, it has been shown that agonism of PPARδ changes the body's fuel preference from glucose to lipids.[21] Initially, PPAR-delta agonists were considered promising therapies as an exercise mimetic that could treatmetabolic syndrome, but later on more evidence was uncovered about their possible pro-cancer effects.[16]
The atypical antidepressantTianeptine has been shown to be a high-efficacy PPAR-delta agonist.[22]
Although its drug development was discontinued due to animal studies suggesting an increased risk of cancer, GW501516 has been used as aperformance enhancing drug.[25] It and other PPAR-delta agonists are banned in sports.[26][27]
^Krey G, Keller H, Mahfoudi A, Medin J, Ozato K, Dreyer C, et al. (December 1993). "Xenopus peroxisome proliferator activated receptors: genomic organization, response element recognition, heterodimer formation with retinoid X receptor and activation by fatty acids".The Journal of Steroid Biochemistry and Molecular Biology.47 (1–6):65–73.doi:10.1016/0960-0760(93)90058-5.PMID8274443.S2CID25098754.
^Feige JN, Gelman L, Michalik L, Desvergne B, Wahli W (March 2006). "From molecular action to physiological outputs: peroxisome proliferator-activated receptors are nuclear receptors at the crossroads of key cellular functions".Progress in Lipid Research.45 (2):120–159.doi:10.1016/j.plipres.2005.12.002.PMID16476485.
^Trevisiol S, Moulard Y, Delcourt V, Jaubert M, Boyer S, Tendon S, et al. (June 2021). "Comprehensive characterization of the peroxisome proliferator activated receptor-δ agonist GW501516 for horse doping control analysis".Drug Testing and Analysis.13 (6):1191–1202.doi:10.1002/dta.3013.PMID33547737.S2CID231899376.
^Sobolevsky T, Dikunets M, Sukhanova I, Virus E, Rodchenkov G (October 2012). "Detection of PPARδ agonists GW1516 and GW0742 and their metabolites in human urine".Drug Testing and Analysis.4 (10):754–760.doi:10.1002/dta.1413.PMID22977012.
^Franco PJ, Li G, Wei LN (August 2003). "Interaction of nuclear receptor zinc finger DNA binding domains with histone deacetylase".Molecular and Cellular Endocrinology.206 (1–2):1–12.doi:10.1016/S0303-7207(03)00254-5.PMID12943985.S2CID19487189.
