PPARa: A Master Regulator of Bilirubin Homeostasis.

Bigo C1, Kaeding J1, El Husseini D1, Rudkowska I2, Verreault M1, Vohl MC3, Barbier O1
Source: Other
Publication Date: (2014)
Issue: 00: 747014
Research Area:
Basic Research
Cells used in publication:
SMC, coronary artery, human (CASMC)
Species: human
Tissue Origin: artery
Hypolipidemic fibrates activate the peroxisome proliferator-activated receptor (PPAR) a to modulate lipid oxidation and metabolism. The present study aimed at evaluating how 3 PPARa 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 PPARa 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 PPARa ligands activate bilirubin synthesis in vascular cells and metabolism in liver cells. The clinical implications of these regulatory events are discussed.