The UDP-glucuronosyltransferase 1A9 Enzyme Is a Peroxisome Proliferator-activated Receptor α and γ Target Gene

Abstract Peroxisome proliferator-activated receptor (PPAR) α and γ are ligand-activated transcription factors belonging to the nuclear receptor family. PPARα mediates the hypolipidemic action of the fibrates, whereas PPARγ is a receptor for the antidiabetic glitazones. In the present study, the UDP-glucuronosyltransferase (UGT) 1A9 enzyme is identified as a PPARα and PPARγ target gene. UGTs catalyze the glucuronidation reaction, which is a major pathway in the catabolism and elimination of numerous endo- and xenobiotics. Among the UGT1A family enzymes, UGT1A9 metabolizes endogenous compounds, including catecholestrogens, and xenobiotics, such as fibrates and to a lesser extent troglitazone. Treatment of human hepatocytes and macrophages and murine adipocytes with activators of PPARα or PPARγ resulted in an enhanced UGT1A9 expression and activity. In addition, disruption of the PPARα gene in mice completely abolished the PPARα agonist-induced UGT1A9 mRNA and activity levels. A PPAR response element was identified in the promoter of UGT1A9 at positions −719 to −706 bp by transient transfection and electromobility shift assays. Considering the role of UGT1A9 in catecholestrogen metabolism, PPARα and PPARγ activation may contribute to the protection against genotoxic catecholestrogens by stimulating their inactivation in glucuronide derivatives. Furthermore, since UGT1A9 is involved in the catabolism of fibrates, these results suggest that PPARα and PPARγ may control the intracellular level of active fibrates.