Contributions of the Ah receptor to bilirubin homeostasis and its antioxidative and atheroprotective functions

The homeostasis and atheroprotective function of bilirubin could be an appealing model to investigate one of the many physiologic functions of the human aryl hydrocarbon receptor (AhR). Several clinical and epidemiological studies have been carried Out on key enzymes generating and eliminating bilirubin (heme oxygenase-1 and UDP-glucuronosyltransferase UGT1A1, respectively) and their regulation by the AhR. Studies with AhR-deficient mice strongly suggest a role of the AhR in vascular biology. Atherosclerosis, a major cause of premature death, is initiated by pro-oxidative insults of the vascular endothelium. The strong antioxidant and activator of AhR bilirubin is generated in vascular endothelial cells, smooth muscles and macrophages. It acts mostly in the lipid environment, thereby complementing other antioxidants such as glutathione which act mostly on water-soluble proteins. In conclusion, the atheroprotective functions of bilirubin might not only provide models to study physiologic functions of the human AhR but also provide opportunities to improve prevention and treatment of a major life-threatening disease.