The catabolism of bilirubin to urobilin might be a leading factor in obesity-induced insulin resistance: New findings in human studies

Abstract

For unknown reasons, plasma bilirubin levels are lower in obese humans and rodents. One possible explanation is that the hepatic expression of enzymes that regulate its half-life, such as the UGT1A1 UDP-glucuronosyltransferase, is higher in the obese compared to lean persons. Bilirubin is marked for excretion within the liver by the conjugation of two glucuronyl groups by UGT1A1, where it is then transported to the intestines by the biliary system. Once in the intestines, the gut microbiota containing bilirubin reductase remove the glucornyl groups and modify the structure to produce urobilin which can be absorbed via the hepatic portal vein and enter the systemic circulation. Previous correlation studies indicate that urobilin might be a factor that induces visceral obesity and cardiovascular disease. However, the physiological function of urobilin is unknown. The purpose of our study was to determine if there is a correlation between bilirubin and urobilin compared to adiposity and insulin resistance in lean and obese women and men. We hypothesized that bilirubin would be lower and urobilin higher in the plasma of obese humans compared to lean. We found that the plasma levels of urobilin and bilirubin are inversely correlated in women and men. Urobilin levels were positively associated with adiposity (BMI R 2 =0.29 and body fat percentage R 2 =0.25) and insulin resistance (blood glucose R 2 =0.05, insulin R 2 =0.22, and HOMA IR R 2 =0.18) in obese women. Urobilin was only correlated with adiposity in males (BMI R 2 =0.025 and body fat percentage R 2 =0.03). However, the males were not insulin resistant and had no significant difference in HOMA IR compared to lean men. In both women (BMI R 2 =0.065 and body fat percentage R 2 =0.05) and men (BMI R 2 =0.24 and body fat percentage R 2 =0.13), plasma bilirubin levels were negatively associated with adiposity. We observed that plasma bilirubin levels are negatively associated with adiposity, which has been previously reported. The new findings in our study indicate that urobilin is positively associated with adiposity and insulin resistance. Based on these data, we propose that bilirubin and urobilin are maintained at inverse levels in humans via the UGT1A1 axis and that activity is higher in the obese, reducing plasma bilirubin and providing more substrates to produce urobilin in the gut. These events cause an elevation in plasma urobilin levels that commence obesity-associated comorbidities. Future work to determine the role of urobilin in obesity-associated comorbidities such as insulin-resistant diabetes is warranted and may provide a biomarker for the early This work was supported by the National Institutes of Health R01DK121797 (T.D.H.J.). The sample collection was supported by the Center for Clinical and Translational Science (CCTS) grant UL1TR001998 at the University of Kentucky. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.