Bilirubin Binding to PPARα Inhibits Lipid Accumulation

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 PPAR alpha. We show that bilirubin can bind directly to PPAR alpha and increase transcriptional activity. When we compared biliverdin, the precursor to bilirubin, on PPAR alpha transcriptional activation to known PPAR alpha 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 PPAR alpha target genes. We treated wild-type and PPAR alpha KO mice on a high fat diet with fenofibrate or bilirubin for seven days and found that both signal through PPAR alpha dependent mechanisms. Furthermore, the effect of bilirubin on lowering glucose and reducing body fat percentage was blunted in PPAR alpha KO mice. These data demonstrate a new function for bilirubin as an agonist of PPAR alpha, which mediates the protection from adiposity afforded by moderate increases in bilirubin.