Abstract
Hypolipidemic fibrates activate the peroxisome proliferator-activated receptor (PPAR) α to modulate lipid oxidation and metabolism. The present study aimed at evaluating how 3 PPARα agonists, namely, fenofibrate, gemfibrozil, and Wy14,643, affect bilirubin synthesis and metabolism. Human umbilical vein epithelial cells (HUVEC) and coronary artery smooth muscle cells (CASMC) were cultured in the absence or presence of the 3 activators, and mRNA, protein, and/or activity levels of the bilirubin synthesizing heme oxygenase- (HO-) 1 and biliverdin reductase (BVR) enzymes were determined. Human hepatocytes (HH) and HepG2 cells sustained similar treatments, except that the expression of the bilirubin conjugating UDP-glucuronosyltransferase (UGT) 1A1 enzyme and multidrug resistance-associated protein (MRP) 2 transporter was analyzed. In HUVECs, gemfibrozil, fenofibrate, and Wy14,643 upregulated HO-1 mRNA expression without affecting BVR. Wy14,643 and fenofibrate also caused HO-1 protein accumulation, while gemfibrozil and fenofibrate favored the secretion of bilirubin in cell media. Similar positive regulations were also observed with the 3 PPARα ligands in CASMCs where HO-1 mRNA and protein levels were increased. In HH and HepG2 cells, both UGT1A1 and MRP2 transcripts were also accumulating. These observations indicate that PPARα ligands activate bilirubin synthesis in vascular cells and metabolism in liver cells. The clinical implications of these regulatory events are discussed.
Highlights
Bilirubin is an endogenous bile pigment produced from heme degradation by the sequential action of the heme oxygenase (HO) and biliverdin reductase (BVR) enzymes
We first tested whether gemfibrozil affects mRNA expression of the bilirubin synthesizing heme oxygenase- (HO-)1 and BVR enzymes in vascular endothelial cells
We investigated whether UGT1A1 and MRP2 expression was responding to gemfibrozil exposure in 2 human liver cell lines
Summary
Bilirubin is an endogenous bile pigment produced from heme degradation by the sequential action of the heme oxygenase (HO) and biliverdin reductase (BVR) enzymes. 2 active isoforms of heme oxygenase, namely, HO-1 and HO-2, convert heme into carbon monoxide, free iron, and biliverdin. This reaction is considered as the ratelimiting step in heme to bilirubin catabolic process [1]. While HO2 is constitutively expressed, HO-1 is encoded by a highly inducible gene activated by a vast variety of endogenous and exogenous stimuli [2]. Genetic polymorphisms causing low HO-1 protein expression are positively associated with increased risk for coronary events [3, 4]
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