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 PPAR Pathway

The peroxisome proliferator-activated receptor (PPAR) family is composed of PPARα, PPARδ (PPARβ, PPARβ/δ, NUC-1/FAAR), PPARγ1, PPARγ2 and the related lipid-activated transcription factors, liver X receptor and farnesoid X receptor. PPARs act as ligand-activated transcription factors that are responsive to the lipid status of the cell. The physiological ligands for these nuclear receptors are typically n-3 and n-6 family unsaturated fatty acids (PUFAs) and their eicosanoid products. PPARs regulate the expression of genes that encode proteins involved with lipid metabolism (oxidation), leukotriene degradation, energy balance, eicosanoid signaling, cell differentiation and tumorigenesis. PPARs are differentially expressed. PPARalpha is highly expressed in liver, kidney, heart, brown adipose tissue, and the intestine, whereas PPARgamma is found in adipose, small intestine, and lymphatic tissues. PPARbeta/delta is ubiquitous. PPARs are generally activated by 18-22 carbon n-3 and n-6 polyunsaturated fatty acid (PUFAs) and eicosanoid products of cyclooxygenase and lipoxygenase. Each PPAR isotype is preferentially activated by specific ligands. For example, leukotriene B4 activates all isotypes, but it activates PPARalpha preferentially. PPARalpha is also activated by arachidonic acid (AA) and fibrates, which links this nuclear factor to atherosclerosis. PPARgamma is activated preferentially by prostaglandins, PG-D1 and PG-D2 and the PG derivative 15-deoxy-Δ12,14-PGJ2 and is linked to antitumor effects. The peroxisome proliferator-activated receptor (PPAR) family belongs to type II subgroup of the steroid receptor superfamily of nuclear transcription factors which also includes the retinoic acid receptor (RAR), vitamin D receptor and thyroid hormone receptor. Members of this group form heterodimers with retinoid X receptor (RXR) isotypes. PPARs typically form heterodimers with RXRalpha (RXRα). PPAR:RXR heterodimers bind to DNA at sites composed of the hexameric direct repeat sequence –AGGRCA- separated by a single nucleotide. PPARs only bind efficiently to DNA when they are associated with RXR, consequently other members of the type II subgroup can compete with PPAR as regulators of gene function. PPARs regulate specific gene activation profiles based upon their relative abundance in the cell, their ability to compete with other factors for access to RXRalpha and the specificity of each PPAR isoform/isotype for its physiological ligand and associated coactivators and costimulators.