Antioxidant bilirubin works in multiple ways to reduce risk for obesity and its health complications

Gilbert syndrome (GS) is a common genetic variant in which plasma unconjugated bilirubin levels are elevated throughout life, in the absence of hepatic pathology.1 This typically reflects decreased hepatic capacity for conjugation of bilirubin coupled with an upregulation of bilirubin generation. Typically, subjects with GS are homozygous for promoter mutations compromising transcriptional efficiency in the gene coding for uridine-diphosphoglucuronate glucuronosyltransferase 1A1 (UGT1A1), which links bilirubin to glucuronic acid; as a result, hepatic expression of this enzyme is decreased, although the enzyme itself is functionally normal. However, plasma bilirubin levels in many people homozygous for such mutations fail to exceed the level (defined as either 17.1 or 20 μmol/L) considered diagnostic for GS. Hence, subjects with GS also are characterised by an increased rate of bilirubin generation, ultimately traceable to increased heme synthesis. In some cases, this may reflect upregulated heme oxygenase activity, which would reflexly boost heme production.1