PPARs were originally identified in Xenopus frogs as receptors that induce the proliferation of peroxisomes in cells. The first PPAR was discovered during the search of a molecular target for a group of agents then referred to as peroxisome proliferators, as they increased peroxisomal numbers in rodent liver tissue, apart from improving insulin sensitivity. These agents, pharmacologically related to the fibrates were discovered in the early 1980s. 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; see below for more details. After PPARδ was identified in humans in 1992, it turned out to be closely related to the PPARβ previously described during the same year in other animals. The name PPARδ is generally used in the US, whereas the use of the PPARβ denomination has remained in Europe where this receptor was initially discovered in Xenopus.
Physiological function
All PPARs heterodimerize with the retinoid X receptor and bind to specific regions on the DNA of target genes. These DNA sequences are termed PPREs. The DNAconsensus 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. The function of PPARs is modified by the precise shape of their ligand-binding domain induced by ligand binding and by a number of coactivator and corepressor proteins, the presence of which can stimulate or inhibit receptor function, respectively. Endogenous ligands for the PPARs include free fatty acids, eicosanoids and Vitamin B3. PPARγ is activated by PGJ2 and certain members of the 5-HETE family of arachidonic acid metabolites including 5-oxo-15-HETE and 5-oxo-ETE. In contrast, PPARα is activated by leukotriene B4. Certain members of the 15-hydroxyeicosatetraenoic acid family of arachidonic acid metabolites, including 15-HETE, 15-HETE, and 15-HpETE activate to varying degrees PPAR alpha, beta/delta, and gamma. PPARγ activation by agonist RS5444 may inhibit anaplastic thyroid cancer growth. See for a review and critique of the roles of PPAR gamma in cancer.
Genetics
The three main forms are transcribed from different genes:
PPARα - chromosome 22q12-13.1
PPARβ/δ - chromosome 6p21.2-21.1
PPARγ - chromosome 3p25.
Hereditary disorders of all PPARs have been described, generally leading to a loss in function and concomitant lipodystrophy, insulin resistance, and/or acanthosis nigricans. Of PPARγ, a gain-of-function mutation has been described and studied which decreased the risk of insulin resistance; it is quite prevalent. In contrast, pro115gln is associated with obesity. Some other polymorphisms have high incidence in populations with elevated body mass indexes.
Structure
Like other nuclear receptors, PPARs are modular in structure and contain the following functional domains:
PPARα and PPARγ are the molecular targets of a number of marketed drugs. For instance the hypolipidemic fibrates activate PPARα, and the anti diabetic thiazolidinediones activate PPARγ. The synthetic chemicalperfluorooctanoic acid activates PPARα while the synthetic perfluorononanoic acid activates both PPARα and PPARγ. Berberine activates PPARγ, as well as other natural compounds from different chemical classes.
