Liver and kidney responses to bilirubin as a nuclear receptor hormone - Summary: The heme metabolite unconjugated bilirubin is toxic at high levels, but also has beneficial effects when slightly elevated within the normal range as seen in Gilbert’s syndrome, with benefits including protection from diabetic kidney disease and chronic kidney disease. These benefits had been attributed exclusively to the antioxidant properties of bilirubin, however several lines of evidence suggest not all bilirubin effects can be explained by antioxidant effects, and bilirubin can trigger receptor-mediated events. Thus, it remains unclear how bilirubin elicits beneficial effects protecting from kidney diseases. We recently discovered unconjugated bilirubin activates Liver Receptor Homolog-1 (LRH-1, NR5A2), a nuclear receptor expressed in the adult human liver and kidneys. A clear role for this new bilirubin-LRH-1 axis has not been established, and LRH-1 functions in the kidney remain almost completely uninvestigated. We hypothesize LRH-1 directly senses bilirubin levels to mediate specific beneficial effects of mildly elevated levels of bilirubin in the human liver and kidneys. A novel approach recently developed by our group permits studying LRH-1 in any human model, including primary human cells. After developing this powerful approach, we now seek to apply it to study diabetic and chronic kidney disease, and in pioneering studies of LRH-1 function in the kidney, which is almost completely uninvestigated. The first aim determines how toxic levels of bilirubin are sensed in primary human hepatocytes to activate basolateral bilirubin efflux pumps, a process that induces jaundice in human patients. The second aim determines how beneficial levels of bilirubin are sensed by human kidney organoids, and will be the most comprehensive analysis of LRH-1 function in the kidney to date. The final aim will determine how nuclear receptors mediate these responses in the liver and the kidneys at the molecular level. Together, this proposal will elucidate how both the toxic and beneficial levels of bilirubin regulate liver and kidney function in primary human cells and organoids, using unique approaches our group has previously developed, and now seek to apply to understanding LRH-1 function in the kidney.
