Bile Acids and Bilirubin in Liver Immunology

Abstract

Primary bile acids are the end product of cholesterol catabolism synthesized in the liver and excreted into bile. Secondary bile acids are derived after modifications of primary bile acids by intestinal microbiota. Historically BAs have been viewed as emulsifying agents facilitating the digestion and absorption of dietary lipids and damaging tissue through their detergent activity. More recent studies have uncovered the hormone-like signaling functions of bile acids that modulate a myriad of metabolic and inflammatory pathways in multiple cell types and tissues via dedicated bile acid receptors in the nucleus (e.g., FXR) and plasma membrane (e.g., TGR5). Accumulating evidence suggests that bilirubin also has active signaling roles in immune cells beyond its well-established antioxidant effects. Deregulated bile acid and bilirubin metabolism and transport have been implicated in the pathogenesis of a variety of diseases including cholestatic and metabolic liver diseases, hepatic malignancies, and inflammatory bowel disease. Although the functions of bile acids and bilirubin in the regulation of inflammation and immunity are only beginning to be appreciated, targeting bile acids and their cellular receptors (e.g., FXR, TGR5) represents an important and highly promising area of drug discovery.