Disorders of bilirubin and lipid metabolism: models and targets of intervention

The increasing prevalence of metabolic disorders as well as increased knowledge about the role of nuclear receptors (NRs) in a plethora of metabolic pathways has led to a surge in the development of drugs targeting these NRs. This thesis aimed to improve our understanding of disorders of bilirubin and lipid metabolism and to find new targets of intervention. Unconjugated hyperbilirubinemia is caused by high amounts of unconjugated bilirubin and this can accumulate in the brain causing damage, which even can lead to death when left untreated. In recent years, a relationship between (mildly) unconjugated hyperbilirubinemia and a beneficial (i.e. anti-atherogenic) lipid profile has been demonstrated. However, this relationship is not yet fully understood and a better understanding of underlying mechanisms will contribute to knowledge about the risk of developing cardiovascular disease. We investigated the relation between bilirubin and lipid metabolism in an animal model for unconjugated hyperbilirubinemia, the Gunn rat. In our studies we demonstrated that activation of two NRs reduced cholesterol levels but did not lower bilirubin levels, and is therefore not a potential therapeutic strategy for unconjugated hyperbilirubinemia.

Peroxisomes are cell organelles involved in metabolism of compounds including cholesterol and fatty acids. The function of many peroxisomal proteins has not been fully elucidated. In this thesis we investigated the metabolic function of the peroxisomal protein PXMP4 under different experimental conditions in a mouse model. The function of PXMP4 is redundant under the tested conditions and is likely compensated for by other peroxisomal proteins.