PPARα: A Master Regulator of Bilirubin Homeostasis

Figure 5

Coordinated regulation of bilirubin synthesis and metabolism by PPARα agonists has antiatherosclerotic effects in the vasculature and normobilirubinemic consequences in the liver. Results presented here suggest that PPARα agonists, such as fenofibrate, gemfibrozil, and Wy14,643, activate the synthesis of bilirubin in the vasculature and its elimination in the liver. In vascular cells (HUVEC and CASMC), fibrates activate PPARα, which in turn binds to PPREs located in the promoter region of the HO-1 gene [20]. This leads to an increased HO-1 expression and heme-to-bilirubin conversion. As a potent antioxidant, bilirubin scavenges reactive oxygen species, and by so exerts atheroprotective effects. In liver cells (hepatocytes), fibrates also activate PPARα, which in turn binds to PPREs located in the promoter region of the UGT1A1 [25] and potentially MRP2 genes (this remains to be established). These regulatory events lead to increased bilirubin-glucuronide production and biliary secretion and by so contribute to reduce systemic accumulation of bilirubin. BVR: biliverdin reductase; CASMC: coronary artery smooth muscle cells; G: glucuronide; HO-1: heme oxygenase-1; HUVEC: human umbilical vein endothelial cells; MRP2: multidrug resistance-associated transporter protein 2; PPAR: peroxisome proliferator-activated receptor; PPRE: PPAR response element; ROS: reactive oxygen species; and UGT1A1: UDP-glucuronosyltransferase 1A1.