Bilirubin Hepatic and Intestinal Transport and Catabolism: Physiology, Pathophysiology, and Benefits

Bilirubin, a metabolite derived from heme degradation, has traditionally been regarded as a waste product and a marker of liver injury. However, increasing evidence suggests that bilirubin also functions as a hormone, and reduced levels are associated with metabolic dysfunction. Studies have shown a strong association between low circulating bilirubin levels and an increased risk of metabolic disorders and cardiovascular disease. To advance bilirubin-based treatment strategies, it is essential to elucidate the mechanisms underlying bilirubin transport and metabolism. Therefore, we provide an in-depth discussion of bilirubin production and its subsequent fates, with a particular focus on the transport between the liver and the intestine. We describe the molecular players involved in heme degradation and biliverdin formation, leading to bilirubin production, followed by its transport from the bloodstream to hepatocytes and from the liver to the intestine. We discuss intestinal bilirubin catabolism, including the microbiome generation of urobilinogen, urobilin, and other metabolites. Finally, we discuss how bilirubin clearance and catabolism intersect with its metabolic effects, highlighting potential therapeutic targets. By integrating these aspects, this review provides a comprehensive understanding of bilirubin's physiological importance, intestinal transport, and breakdown, as well as insights into novel strategies for treating hypobilirubinemia-associated disorders.