Bilirubin, a Cardiometabolic Signaling Molecule

Mostly considered as a marker for hepatic disease, bilirubin, has been revealed as a cardio and metabolic protective factor that has implications for therapy. Reports of bilirubin date back to ancient Greek medicine with Hippocrates and the four humors of human health, which metabolic agents included Choleric-yellow bile, Melancholic-black bile, Sanguine-blood, and Phlegmatic-phlegm. The yellow bile was associated with the gallbladder and black bile the spleen. These intricacies are still under consideration today. Serum levels of bilirubin are thought to be derived from the breakdown of red blood cells that mostly occurs in the spleen. Bilirubin is a naturally occurring product from the catabolism of heme by heme oxygenase (HO), which releases biliverdin, carbon monoxide (CO), and iron1, 2. Then, biliverdin is reduced to bilirubin via biliverdin reductase (BVR). Bilirubin is released into the blood and binds albumin where it travels to other organs or is deposited in the liver and conjugated with glucuronic acid by the UDP-glucuronosyltransferase 1A1 (UGT1A1) enzyme 3, 4 Conjugated bilirubin (CBR) is excreted from the liver to bile in the gallbladder and eventually released into the intestine where it is broken down by the gut microbiota into urobilinoids, mainly stercobilin, which is the predominant pigment in feces 3. High blood levels of unconjugated bilirubin (UCB) is most widely known as the causative agent of jaundice, a yellowing of the skin and eyes. Neonatal jaundice has been described in the medical literature since the late eighteenth century and is a condition reflective of very high levels of UCB in the serum of newborn infants. Severe cases of neonatal jaundice have resulted in a bilirubin-induced neurological condition in newborns known as kernicterus, which can cause brain damage. Despite its role in jaundice, UCB has several beneficial effects on the body 5. The results of numerous large-scale population and epidemiological studies have correlated a protective effect of serum bilirubin levels against cardiovascular and metabolic disease. However, the molecular mechanism by which this occurs is not fully understood. The objective of this review is to highlight and discuss the unique signaling actions of BVR generation of bilirubin and how they signal to protect against cardiovascular and metabolic disease, which may lead to new therapeutics.