The loss of the hormonal function of bilirubin induces adiposity in male and female mice

The prevalence of obesity and its related comorbidities, including diabetes and metabolic dysfunction associated fatty liver disease (MAFLD), are on the rise globally, indicating the importance of new therapeutics for these diseases. Interestingly, serum bilirubin levels are negatively correlated with obesity, diabetes, and MAFLD. We have previously generated pegylated bilirubin nanoparticles (PEGBR) and demonstrated their therapeutic potential in the treatment of obesity and MAFLD. However, it’s unknown whether their beneficial effects are due to bilirubin’s antioxidant properties or its hormonal function by binding to and activating the nuclear receptor peroxisome proliferator-activated receptor alpha (PPARa). To determine this, we used female and male hepatocyte-specific PPARa knockout mice ( PparaHepKO) and floxed ( Pparaflox) control mice on a high-fat diet for 30 weeks to induce adiposity and MAFLD. The mice were treated with vehicle or PEGBR (30 mg/kg) for six weeks. In female Pparaflox mice, PEGBR significantly lowered body weight, but not in the female PparaHepKO mice. A similar trend was seen in the male Pparaflox mice but was not statistically significant. PEGBR significantly reduced hepatic fat mass and triglycerides in the female and male Pparaflox mice but not in the PparaHepKO mice. Using lipidomics, we determined the lipid composition of the liver and how PEGBR changed it. In the male Pparaflox mice, PEGBR significantly reduced 109 lipid species, whereas, in the male PparaHepKO mice, PEGBR only reduced 7 species (93.6% reduction). In the female PparaHepKO mice, there was a 2.7% reduction in the number of lipid species significantly decreased by PEGBR compared to Pparaflox controls. Male Pparaflox mice had an increase in plasma high-density lipoprotein cholesterol and a decrease in very-low-density particle number with PEGBR, but this was not seen in the male PparaHepKO or female mice. In addition to protecting against the development of MAFLD, PEGBR significantly reduced fasting blood glucose and insulin levels only in the Pparaflox mice. Overall, the data indicates that the protective effects of bilirubin on obesity, MAFLD, and glucose tolerance are due to its hormonal function through PPARa. This study also confirms the therapeutic potential of bilirubin nanoparticles for obesity and its associated comorbidities. This work was supported by the National Institutes of Health F31HL170972 (Z.A.K.) and R01DK121797 (T.D.H.J.) and R01DA058933 (T.D.H.J.). This is the full abstract presented at the American Physiology Summit 2024 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.