PPARs were originally identified in Xenopus frogs as receptors that induce the proliferation of peroxisomes in cells in 1992.[7]
The first PPAR (PPARα) was discovered in 1990 during the search for a molecular target of a group of agents then referred to as peroxisome proliferators, as they increased peroxisomal numbers in rodent liver tissue, apart from improving insulin sensitivity.[8]
When it turned out that PPARs played a much more versatile role in biology, the agents were in turn termed PPAR ligands. The best-known PPAR ligands are the thiazolidinediones.
After PPARδ (delta) was identified in humans in 1992,[9] it turned out to be closely related to PPARβ (beta), previously described during the same year in an amphibian, Xenopus. The term "PPARδ" is generally used in the US, whereas the use of "PPARβ" has remained in Europe, where this receptor was initially discovered in Xenopus.
PPARs were so-named because they were discovered to induce peroxisome proliferation in rodents, but this induction of peroxisome proliferation is not believed to occur in humans.[10][11]
Physiological function
All PPARs heterodimerize with the retinoid X receptor (RXR) and bind to specific regions on the DNA of target genes. These DNA sequences are termed PPREs (peroxisome proliferator hormone response elements). The DNA consensus sequence is AGGTCANAGGTCA, with N being any nucleotide. In general, this sequence occurs in the promoter region of a gene, and, when the PPAR binds its ligand, transcription of target genes is increased or decreased, depending on the gene. The RXR also forms a heterodimer with a number of other receptors (e.g., vitamin D and thyroid hormone).
The function of PPARs is modified by the precise shape of their ligand-binding domain (see below) induced by ligand binding and by a number of coactivator and corepressor proteins, the presence of which can stimulate or inhibit receptor function, respectively.[12]
Endogenous ligands for the PPARs include free fatty acids, eicosanoids and Vitamin B3. PPARγ is activated by PGJ2 (a prostaglandin) and certain members of the 5-HETE family of arachidonic acid metabolites including 5-oxo-15(S)-HETE and 5-oxo-ETE.[13] In contrast, PPARα is activated by leukotriene B4. Certain members of the 15-hydroxyeicosatetraenoic acid family of arachidonic acid metabolites, including 15(S)-HETE, 15(R)-HETE, and 15-HpETE activate to varying degrees PPAR alpha, beta/delta, and gamma. In addition, PPARγ was reported to be involved in cancer pathogenesis and growth.[14][15]PPARγ activation by agonist RS5444 may inhibit anaplastic thyroid cancer growth.[16] See[17] for a review and critique of the roles of PPAR gamma in cancer.
Genetics
The three main forms of PPAR are transcribed from different genes:
^Dreyer C, Krey G, Keller H, Givel F, Helftenbein G, Wahli W (1992). "Control of the peroxisomal beta-oxidation pathway by a novel family of nuclear hormone receptors". Cell. 68 (5): 879–87. doi:10.1016/0092-8674(92)90031-7. PMID1312391. S2CID3148132.