The peroxisome proliferator-activated receptors act as nuclear transcription factors and occur in three different forms, PPAR-alpha, PPAR-delta and PPAR-gamma. When activated, these receptors regulate the expression of genes involved in a variety of metabolic pathways. PPARα-regulated target genes are centrally involved in the metabolism of fatty acids. Specific PPARα effects include an increase in fatty acid oxidation in peroxisomes and mitochondria. Additional evidence indicates that PPARα activation leads to a variety of anti-inflammatory effects. Known activators include fibrates, in use clinically, as well as herbicides and phthalate plasticizers (Reddy, et al., Crit. Rev. Toxicol. 12:1-58 (1983)).
The PPAR-alpha receptor has been isolated and is known to be activated by fatty acids (Isseman, et al., Nature 347:645-650 (1990); Gottlicher, et al., Proc. Nat'l Acid. Sci. USA 89:4653-4657 (1992); Tugwood, et al., EMBO J. 11:433-439 (1992); Bardot, et al., Biochem. Biophys. Res. Comm. 192:37-45 (1993); Muerhoff, et al., J. Biol. Chem. 267:19051-19053 (1992); Marcus, et al., Proc. Nat'l Acid. Sci. USA 90:5723-5727 (1993)). There have been suggestions that activators of this receptor may be useful in treating skin conditions (U.S. Pat. No. 6,060,515) and obesity (U.S. Pat. No. 6,028,109). In addition, at least one report has suggested that activators of the gamma form of PPAR may be useful in treating inflammatory skin conditions (U.S. Pat. No. 5,981,586). A better understanding of the way in which the PPAR receptors are activated, especially in terms of endogenous pathways, may lead to new and better approaches to therapy.