PPARα: A Master Regulator of Bilirubin Homeostasis

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.

Rats Genetically Selected for High Aerobic Exercise Capacity Have Elevated Plasma Bilirubin by Upregulation of Hepatic Biliverdin Reductase-A (BVRA) and Suppression of UGT1A1

“…Others have proposed that PPARα may regulate bilirubin homeostasis [67]. These observations suggest a possible feedback loop for bilirubin-PPARα, which might be a fundamental circuit for exercise.…”

“…There has been a correlation for palmitoylethanolamide (PEA) and oleoylethanolamine (OEA), which are natural PPARα ligands derived from fatty acids, and their activation of PPARα may regulate bilirubin levels [ 66 ]. Others have proposed that PPARα may regulate bilirubin homeostasis [ 67 ]. These observations suggest a possible feedback loop for bilirubin-PPARα, which might be a fundamental circuit for exercise.…”

Features of an altered AMPK metabolic pathway in Gilbert’s Syndrome, and its role in metabolic health

“…So far, there is no literature available on a possible role for the UGT1A1 * 28 polymorphism and/or elevated levels of UCB in these complex regulations. As yet, only one recent study 31 points out a connection between circulating bilirubin (BR) and Ppar α, using an in vitro approach. This very report expands the field of known physiological bilirubin functions and activities, including antioxidant 32 , immune-modulating 33 and signalling effects, the latter of which have been investigated in terms of Ppar activities in BR-treated mice.…”

Total Bilirubin Yields Prognostic Information Following a Myocardial Infarction in the Elderly

“…Investigations based on cell cultures indicate that PPARα activators, such as fenofibrate and gemfibrozil, regulate genes controlling bilirubin synthesis in vascular cells and its metabolism in hepatic cells [ 32 ], providing beneficial antiatherosclerotic effects, essentially by the upregulation of HMOX1. Furthermore, it has been demonstrated that patients with Gilbert’s polymorphism and higher bilirubin levels are less affected by metabolic disorders, such as obesity and type 2 diabetes mellitus [ 2 , 33 , 34 ].…”