Bilirubin Binding to PPARα Inhibits Lipid Accumulation.

David E Stec,Terry D Hinds,Kezia John,Michael W Hankins,Christopher J Trabbic,Justin Baum,Amarjit Luniwal,Hervé Guillou

doi:10.1371/journal.pone.0153427

David E Stec, Terry D Hinds + Show 6 more

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https://doi.org/10.1371/journal.pone.0153427

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Abstract

Numerous clinical and population studies have demonstrated that increased serum bilirubin levels protect against cardiovascular and metabolic diseases such as obesity and diabetes. Bilirubin is a potent antioxidant, and the beneficial actions of moderate increases in plasma bilirubin have been thought to be due to the antioxidant effects of this bile pigment. In the present study, we found that bilirubin has a new function as a ligand for PPARα. We show that bilirubin can bind directly to PPARα and increase transcriptional activity. When we compared biliverdin, the precursor to bilirubin, on PPARα transcriptional activation to known PPARα ligands, WY 14,643 and fenofibrate, it showed that fenofibrate and biliverdin have similar activation properties. Treatment of 3T3-L1 adipocytes with biliverdin suppressed lipid accumulation and upregulated PPARα target genes. We treated wild-type and PPARα KO mice on a high fat diet with fenofibrate or bilirubin for seven days and found that both signal through PPARα dependent mechanisms. Furthermore, the effect of bilirubin on lowering glucose and reducing body fat percentage was blunted in PPARα KO mice. These data demonstrate a new function for bilirubin as an agonist of PPARα, which mediates the protection from adiposity afforded by moderate increases in bilirubin.

Highlights

Recent investigations have revealed that increased bilirubin levels are positively associated with a leaner phenotype and are protective of the vasculature system
We have recently shown that increasing the production of bilirubin in obese mice resulted in the elevation of the fat burning nuclear receptor, PPARα, reducing body weight and blood glucose [16]
Bilirubin plasma levels have been shown to be inversely correlated with lipid and glucose, and increasing levels have been shown to be beneficial for obesity, type II diabetes, and cardiovascular disease

Summary

Introduction

Recent investigations have revealed that increased bilirubin levels are positively associated with a leaner phenotype and are protective of the vasculature system. Beyond functioning as an antioxidant [1], bilirubin has no known physiologic function. Water-insoluble, unconjugated bilirubin normally travels through the bloodstream to the liver, where it is converted into a water-soluble, conjugated form by the uridine diphosphate glucuronyltransferase (UGT) system and excreted into bile [2]. Mutations in the UGT system result in elevated plasma levels of unconjugated bilirubin.

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