Regulation of Sulfotransferase and UDP-Glucuronosyltransferase Gene Expression by the PPARs
Regulation of SULT and UGT gene transcription by PPAR . The PPAR and RXR nuclear receptors are each depicted as a zinc module-containing DNA-binding domain (rectangle) that is joined to a ligand-binding domain (LBD, triangle) through a hinge region. PPAR and RXR bind as a heterodimer to a peroxisome proliferator response element (PPRE) in the regulatory region of a target gene. The consensus PPRE is a nuclear receptor hexamer motif (i.e., (A/G)G(G/T)TCA) in a DR-1 configuration (direct repeat with one intervening nucleotide, N). Binding of an agonist to the LBD of PPARα (e.g., chemical structure for the potent PPAR agonist, ciprofibrate, is shown) evokes a conformational change in the receptor that results in coactivator recruitment and increased target gene transcription. In contrast to its silent role in partnership with some nuclear receptors, RXR functions as an active partner with the PPARs, whereby binding of an agonist to the LBD of RXR (e.g., chemical structure for the prototype RXR ligand, 9-cis -retinoic acid, is shown) activates target gene transcription and enhances PPAR ligand-activated transcription. The locations of functional PPREs that have been identified in the -flanking regions of the human SULT2A1 , UGT1A1 , UGT1A3 , UGT1A6 , UGT1A9, and UGT2B4 genes are shown (positions are relative to the transcription start site).
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