Novel strategies to investigate lipoprotein metabolism and combat cardiometabolic disease

Abstract

Atherosclerotic cardiovascular disease (ASCVD) and metabolic dysfunction-associated steatotic liver disease (MASLD; previously known as non-alcoholic fatty liver disease) are a result of lipid accumulation in the vascular wall and liver, respectively. In the body, lipids are transported between organs within lipoproteins, and thus disordered lipoprotein metabolism is closely associated with ASCVD and MASLD development. Active brown adipose tissue (BAT) combusts lipids to produce heat, and BAT activation is therefore considered a potential strategy to improve lipoprotein metabolism. In this thesis, I describe a new method of monitoring lipoprotein metabolism and BAT activity by PET-CT scan. To this end, a newly developed 18F-labeled lipid tracer was incorporated in optimized lipoprotein-like particles, and appeared to outperform 18F-deoxyglucose in tracing activated BAT. The results presented in this thesis also further confirm the usefulness of the APOE*3-Leiden.CETP mouse model for studying therapeutic interventions to improve lipoprotein metabolism. Using this translational model, I demonstrated that exercise at the end of the active phase and combined glucose-dependent insulinotropic polypeptide receptor and glucagon-like peptide receptor agonism, a strategy for treating diabetes and obesity in the clinic, are promising ways to combat both ASCVD and MASLD.