Abstract
Peroxisome proliferator-activated receptor (PPAR) alpha and gamma are ligand-activated transcription factors belonging to the nuclear receptor family. PPAR alpha mediates the hypolipidemic action of the fibrates, whereas PPAR gamma is a receptor for the antidiabetic glitazones. In the present study, the UDP-glucuronosyltransferase (UGT) 1A9 enzyme is identified as a PPAR alpha and PPAR gamma 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 PPAR alpha or PPAR gamma resulted in an enhanced UGT1A9 expression and activity. In addition, disruption of the PPAR alpha gene in mice completely abolished the PPAR alpha 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, PPAR alpha and PPAR gamma 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 PPAR alpha and PPAR gamma may control the intracellular level of active fibrates.
Highlights
Fatty acids and derivatives are natural ligands for Peroxisome proliferator-activated receptor (PPAR)␣ and Peroxisome proliferator-activated receptors (PPARs)␥
Since UGT1A9 is involved in the catabolism of fibrates, these results suggest that PPAR␣ and PPAR␥ may control the intracellular level of active fibrates
UGT1A9 Catalyzes Glucuronidation of Fibrates and Troglitazone—Recent studies have indicated that UGT1A9 catalyzes glucuronidation of gemfibrozil, fenofibric acid, and troglitazone, suggesting that this enzyme is involved in the metabolism of synthetic PPAR activators [22,23,24,25]
Summary
Fatty acids and derivatives are natural ligands for PPAR␣ and PPAR␥. Natural eicosanoids derived from arachidonic acid via the lipoxygenase pathway, such as 8-hydroxytetraenoic acid (8-HETE), 15-HETE, and leukotriene B4, as well as oxidized phospholipids activate PPAR␣ [7,8,9]. The hypolipidemic fibrates (gemfibrozil, bezafibrate, ciprofibrate, and fenofibrate) are PPAR␣ ligands [7] Both natural and synthetic ligands of PPARs share similar metabolic pathways, since eicosanoids, fibrates, and troglitazone are excreted as glucuronide conjugates in humans [11,12,13,14]. Clofibrate induces the glucuronidation of an antithrombotic thioxyloside (LF 4.0212), which is catalyzed by UGT1A9 in humans [30] Based on these observations, we investigated in the present study whether UGT1A9 expression is regulated by PPAR␣ and PPAR␥ agonists. Induction of UGT1A9 gene expression is accompanied by an increased glucuronidation activity of catecholestrogens and fibrates This positive regulation of UGT1A9 expression occurs at the transcriptional level by binding of PPAR␣ and PPAR␥ to a DR1 response element located at Ϫ719 to Ϫ706 bp in the promoter region of the UGT1A9 gene. The role of PPAR␣ in the fibrate-dependent induction of UGT1A9 is established by the absence of fibrate response in PPAR␣-null mice
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