Bilirubin: A ligand of the pparα nuclear receptor

Bilirubin is the product from red blood cell lysis, which releases heme that is reduced to biliverdin by heme oxygenases (HO). Later, the biliverdin is converted to bilirubin by the biliverdin reductase (BVR) enzyme. Studies have revealed that bilirubin is significantly lower in obese patients with nonalcoholic fatty liver disease (NAFLD). While the mechanisms that reduce plasma bilirubin are unknown, it has been shown that increasing plasma bilirubin lowers body fat percentage and liver fat content in obese animal models. The bilirubin actions have been attributed to a newly revealed function that it is a hormone, which binds directly to the PPARα nuclear receptor transcription factor. PPARα regulates fatty acid oxidation (FAO) and peroxisomal function to maintain cellular homeostasis and catabolism of fatty acids. Here, we discuss the partnership of bilirubin-PPARα, along with the two other PPAR isoforms PPARβ/δ and PPARγ, and how they function to control peroxisomes and mitochondria that mediates fatty acid β-oxidation and adiposity. There may be clinical interest in bilirubin-PPARα functionality to rectify NAFLD and insulin resistance in the obese.