Bilirubin and Metabolic Health
Funding Body: FWF-Austrian Science Fund, Project No. P36259
Duration: 2023-2025
Principal Investigator:
Karl-Heinz Wagner
Main Project group:
TbA
Cooperation partners:
Assoc. Prof. Dr. Martin Krssak, Medical University, Vienna
Assoc. Prof. Dr. Florian Kiefer, Medical University, Vienna
Prof. Dr. Andrew Bulmer, Griffith University, Australia
Univ. Prof. Dr. Daniel König, University of Vienna
Short description:
Mildly elevated serum bilirubin concentrations, such as those seen in individuals with Gilbert’s syndrome (GS, prevalence 5-10%), may protect against chronic metabolic diseases. Very recent data from us show that the enhanced lipid catabolism in GS seems to be one of the key mechanisms involved. Based on these very preliminary observations, and the strong link between bilirubin metabolism and metabolic health, we aim to investigate here more deeply mechanistic questions to better understand why GS subjects show the specific phenotype and its metabolic potential.
Due to the high prevalence of GS, the understanding of how bilirubin metabolism is interacting with metabolic health and - flexibility is highly significant. We will target novel mechanisms by applying highly sophisticated assessment/imaging tools. We will thereby generate and link human with animal data to 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 (OGTT) and a bike ramp test to measure FATmax). The human studies will be complemented by a recently established very new cre-floxUGT1A1 mouse model, which is optimal suited to determining whether we can prevent or arrest/reverse metabolic effects of obesity/metabolic syndrome after it is developed by bilirubin.
First, we will perform a case control study (GS vs. controls) with direct measurements of fat accumulation/lipid quality in the liver and the muscle (1H MRS, 31P MRS, and MRI imaging) as well as the brown adipose tissue (BAT) activity with PET. The two metabolic flexibility studies will be performed with either an OGTT or a bike test to measure FATmax. In both studies, indirect calorimetry as well as metabolomic (one focus are sugar metabolomics) and free fatty acids will be used to evaluate the metabolic state. The novel mouse model will permit induction of a GS phenotype during adolescence (similar to humans), to investigate whether UGT1A1 knockdown can prevent obesity and dietary induced obesity/diabetes.
This project is highly novel: -) to date there are no studies published which link GS to metabolic flexibility in humans; -) we will use two metabolic challenges, OGTT and a bike test, which will generate novel data; -) we will measure metabolic flexibility with metabolomics, specifically sugar metabolomics and with indirect calorimetry; -) this will be the first study in humans regarding the direct measurement of fat accumulation/lipid quality in the liver and the muscle as well as the brown adipose tissue; -) we will use a recently established, very new cre-floxUGT1A1 mouse model.
