Bilirubin and Metabolic Health

Bile pigments are naturally occurring compounds formed in the human body. The main pigments, called bilirubin and biliverdin, are intensely colored and can been seen in the skin during jaundice (bili- rubin) and in the green (biliverdin) and yellow (bilirubin) color of bruises. In the past, bile pigments and bilirubin in particular have been thought of useless or even harmful compounds since jaundice particu- larly in babies is associated with diseases and occasionally can be toxic. Today their positive effects on the organism especially in adults are proven, mainly as antioxidants. Recent data from us and other research groups have shown that mildly elevated blood bilirubin con- centrations (unconjugated bilirubin; UCB), such as those typically seen in individuals with Gilberts syndrome (GS, benign hyperbilirubinemia, prevalence 5-10%), may protect against diseases associated with increased oxidative stress such as cardiovascular disease or type 2 diabetes, improve the immune response and reduce metabolic dysfunction. Interestingly people with GS are leaner, have a lower body mass index and an improved lipid metabo- lism (e.g. lower total and LDL-cholesterol compared to the general population), an observation which is even more pronounced in older subjects. Based on these very preliminary observations, and the strong link between bilirubin metabolism and metabolic health we aim to investigate in this project more deeply mechanistic questions to better understand why GS subjects show the very specific outcomes in the body and its metabolic potential. We will thereby generate and link human with animal data and bring them together to even better understand the complex metabolic interactions. The application is based on one human case control study and two human metabolic flexibility studies (Glucose-tolerance-test and a bike ramp test to measure the maximal fat oxidation). The human studies will be complemented by a recently estab- lished a very new cre-floxUGT1A1 mouse model, which is best suited to determining whether we can prevent or arrest/reverse metabolic effects of obesity/metabolic syndrome after it is developed by bilirubin. Our study will also be the first study in humans regarding the direct measurement of fat accumula- tion/lipid quality in the liver and the muscle as well as the brown adipose tissue.