A Novel Perspective on the Biology of Bilirubin in Health and Disease

Unconjugated bilirubin (UCB) is known to be one of the most potent endogenous antioxidant substances. While hyperbilirubinemia has long been recognized as an ominous sign of liver dysfunction, recent data strongly indicate that mildly elevated bilirubin (BLB) levels can be protective against an array of diseases associated with increased oxidative stress. These clinical observations are supported by new discoveries relating to the role of BLB in immunosuppression and inhibition of protein phosphorylation, resulting in the modulation of intracellular signaling pathways in vascular biology and cancer, among others. Collectively, the evidence suggests that targeting BLB metabolism could be considered a potential therapeutic approach to ameliorate a variety of conditions.

TrendsHistorically known for its toxicity but recently recognized as a powerful protective molecule, BLB is gaining more attention due to its pleiotropic biomolecular effects and those of the enzymes involved in BLB metabolism (the ‘Yellow Players’).Both heme oxygenase (HMOX) and biliverdin reductase (BLVR) (the main enzymes in BLB metabolism) act on numerous signaling pathways, with unsuspected biological consequences. The interconnections of such pathways highlight an incredibly complex biomolecular network. Yellow player molecules can have important physiological and pathological biological outcomes. Their still unexplored roles merit attention, offering the possibility of being targeted for therapeutic benefit.The moderately high levels of UCB in the blood of patients with Gilbert syndrome are suggestive of the protective role of BLB in non-neurological pathologies (cardiovascular diseases, cancer, and metabolic syndrome).Cells and tissues might actively maintain the intracellular homeostasis of BLB, with the yellow players being viewed as novel antioxidant mechanisms in a cell.This new point of view might also be applicable to neurological diseases, where BLB levels are lower than in healthy subjects.