Peroxisome proliferator-activated receptor
In the field of molecular biology, the peroxisome proliferator-activated receptors (PPARs) are a group of nuclear receptor proteins that function as transcription factors regulating the expression of genes. PPARs play essential roles in the regulation of cellular differentiation, development, and metabolism (carbohydrate, lipid, protein), and tumorigenesis of higher organisms. Nomenclature and tissue distribution. Three types of PPARs have been identified: alpha, gamma, and delta (beta): History. PPARs were originally identified in "Xenopus" frogs as receptors that induce the proliferation of peroxisomes in cells. The first PPAR (PPARα) was discovered 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. 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 (delta) was identified in humans in 1992, 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. 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. Endogenous ligands for the PPARs include free fatty acids, eicosanoids  and Vitamin B3. PPARγ is activated by PGJ (a prostaglandin) and certain members of the 5-HETE family of arachidonic acid metabolites including 5-oxo-15(S)-HETE and 5-oxo-ETE. In contrast, PPARα is activated by leukotriene B. 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. 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 of PPAR are transcribed from different genes: Hereditary disorders of all 3 of these 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: Pro12Ala, which decreases the risk of insulin resistance. It is quite prevalent, with an allele frequency of 0.03 - 0.12 in some populations. In contrast, pro115gln is associated with obesity. Certain other polymorphisms in PPAR show a 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: The DBD contains two zinc finger motifs, which bind to specific sequences of DNA known as hormone response elements when the receptor is activated. Pharmacology and PPAR modulators. 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 chemical perfluorooctanoic 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. Peroxisome