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PPAR Research
Volume 2014, Article ID 747014, 11 pages
http://dx.doi.org/10.1155/2014/747014
Research Article

PPARα: A Master Regulator of Bilirubin Homeostasis

1Laboratory of Molecular Pharmacology, CHU de Québec Research Centre and Faculty of Pharmacy, Laval University, Québec, QC, Canada G1V 4G2
2Endocrinology and Nephrology, CHU de Québec Research Center, Québec, QC, Canada G1V 4G2
3Institute of Nutraceuticals and Functional Foods (INAF), Laval University, Québec, QC, Canada G1V 0A6

Received 28 February 2014; Revised 11 June 2014; Accepted 11 June 2014; Published 23 July 2014

Academic Editor: Howard P. Glauert

Copyright © 2014 Cyril Bigo et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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.