BiliMetHealth- Energy Metabolism and Brown Adipose Tissue (BAT) Activity in Individuals With Gilbert's Syndrome (GS) and Healthy Controls

Bilirubin has long been associated with liver pathology and haemolytic conditions and was until recently assumed to possess little or no biological function. However, unconjugated bilirubin (UCB) rarely approaches these toxic levels and approximates 10 μM in the general population, which is 30-60 times below the reported toxic threshold.

The beneficial associations of mildly elevated blood UCB concentrations with diseases of civilization (in particular those affecting the cardiovascular system and all-cause mortality) have been reported in numerous studies. In addition, a mildly elevated UCB is also associated with reduced adiposity, decreased risk of metabolic syndrome, non-alcoholic fatty liver disease and diabetes as well as overall cancer risk. Bilirubin downregulates pro-inflammatory responses often observed in disease, which complements epidemiological evidence of reduced inflammatory, autoimmune, and degenerative diseases in individuals with GS. Together, these observations may account for the reduced all-cause mortality rates reported in those with GS compared to the normobilirubinaemic population. Finally, bilirubin has been recently reported to modulate cell signalling and act as an endocrine molecule. We were amongst the first to show that - bile pigments possess substantial anti-mutagenic in vitro and ex vivo antioxidant capacity; - subjects with mild hyperbilirubinaemia - also called Gilbert ́s Syndrome (GS) have a significantly reduced BMI compared to age and gender matched controls, a lower hip circumference (HC) as well as lower total/LDL cholesterol, triglycerides and low- and pro-atherogenic sub fractions as well as IL-6. Interestingly effects of GS in older participants (≥35yrs) is most profound, with substantially reduced anthropometric data and improved lipid profile.

Very recently we and others showed that enhanced lipid catabolism in GS seems to be the key mechanism involved.

Based on these very preliminary observations, and the strong link between bilirubin metabolism and metabolic health we aim to investigate in this application more deeply mechanistic questions to better understand why GS subjects show the very specific phenotype and its metabolic potential.

Here we propose a human case control study. Therefore we will investigate 40 GS individuals vs. 40 age and gender matched controls. Participants will be recruited as performed in previous studies.