Role of Metabolic Lipases in Platelets

Although prevention of bleeding is the central role of platelets, they contribute to processes beyond hemostasis and thrombosis. Findings in human platelets and in animal models suggest that platelets may be critical components of the immune system and therefore may contribute to a variety of diseases, including atherosclerosis. The principal goal of this project is to understand the role of lipases in platelets. In most cell types, degradation of lipid droplets by lipases (lipolysis) represents an important biochemical mechanism to generate free fatty acids, which are further used as energy substrates, precursors for lipid and membrane synthesis, and ligands for various signaling processes. Utilizing lipase-deficient mice, this proposal aims at investigating how the expression of lipases in platelets regulates platelet metabolism, with specific focus to platelet aggregation and shape change, platelet lipid composition and plasma concentrations of pro- and anti- inflammatory lipid mediators, pathways that might be involved, and the consequences of platelet-specific lipase deficiencies on atherosclerosis susceptibility. The proposed application will evaluate the role of lipases in platelet physiology, activation, and thrombus formation and will advance our understanding of how lipolysis affects cellular lipid metabolism. Results from this project are expected to identify signaling pathways and points of therapeutic intervention, such as potential targets for the development of novel drugs for the regulation of intravascular platelet activation.

In addition to their primary role of preventing bleeding, platelets are involved in processes beyond hemostasis and the formation of a blood clot (thrombus). Platelets are now thought to be critical components of the immune system and are involved in a wide variety of diseases, including atherosclerosis. The goal of this project was to better understand the role of lipases in platelets. In many cell types, the degradation of lipid droplets by lipase (lipolysis) represents an important biochemical mechanism to provide fatty acids, which are used as energy substrates and as important molecules in various metabolic pathways. We therefore investigated the influence of lipases on platelet metabolism, with particular attention to their aggregation, shape change and lipid composition, the metabolic pathways involved, and the consequences of the deficiency of certain lipases on thrombus formation. Our results deepened our understanding of how lipases affect cellular lipid metabolism and that lipases have a significant role in the development of thrombosis.