Abstract

The inverse relationship between the levels of HDL cholesterol (HDL-C) and the risk of cardiovascular disease has been established for a long time. However, clinical trials that pharmacologically elevate HDL-C showed no clinical benefits. The HDL metric used by clinical laboratories - the amount of cholesterol - is limited, since it does not provide information about composition (except cholesterol content) and function of HDL. Evidence obtained with cellular and animal models and in humans support the proposal that HDL can be converted to a dysfunctional particle with significant impairment of its protective roles. However, the causes and mechanisms of this transformation remain poorly understood. The purpose of this proposal is to identify the mechanisms that promote the formation of dysfunctional HDL and the cellular consequences of this transformation. To achieve this goal will be used multiple approaches, starting with cell models especially developed to assess the functionality of HDL. Preliminary results demonstrated that lipoproteins lose their functions in a dyslipidemic environment. In this way, using an animal model of hyperlipidemia and insulin resistance, we will search for proteins with altered expression and abundance in the lipoproteins of these animals and correlate these quantitative proteomics data with functional studies. Moreover, these studies will be extended to patients with Type 2 Diabetes who have diabetic dyslipoproteinemia, a condition characterized by low levels of HDL-C and high levels of triglycerides. Through shotgun and quantitative proteomics, we will look for biomarkers of dysfunctionality in lipoproteins of these patients, and correlate these findings with functional studies. Our studies can promote a significant advance in the understanding of the pathways that make the lipoproteins dysfunctional in dyslipidemias. (AU)