| Plasma levels of HDL cholesterol are invariably found to be inversely associated with the risk of atherosclerotic cardiovascular disease. This protective effect of HDL has classically been ascribed to HDL-mediated reverse cholesterol transport (RCT), i.e. HDL providing carrier capacity for the transport of excess cholesterol from the periphery back to the liver for subsequent excretion into bile. However, recent data derived from the literature as well as generated by the applicant indicate that RCT might not represent the main atheroprotective property of HDL. Rather, bioactive molecules contained within HDL seem to play a major but thus far largely underexplored role. Therefore, the major underlying hypothesis of this proposal is that biologically active lipid mediators contained within the HDL particle impact on vessel wall function as well as on hepatic cholesterol metabolism and that these functions are mediated via the HDL receptor SR-BI. Using different genetically engineered mouse models and a set of SR-BI mutants the impact of defined HDL sterols on endothelial dysfunction (PhD project 1), an antecedent of clinical cardiovascular disease, and biliary cholesterol excretion (PhD project 2), to date the only known pathway for irreversible removal of cholesterol from the body, will be explored. Kinetic studies will further help to differentiate between uptake and signalling functions of SR-BI. A metabolomics screen combined with in vitro reporter systems and microarray technology will be performed to identify and functionally characterize all possible lipid mediators contained within HDL. The results of these experiments will conceivably contribute to a shift of paradigm in the field of lipoprotein and atherosclerosis research and are further expected to initiate novel HDL-based therapeutic strategies. |
