The storage and mobilization of lipid are fundamental cellular processes, and its dysregulation contributes to numerous diseases including diabetes, atherosclerosis and cardiomyopathy. The central hypothesis of this proposal is that regulated lipolysis involves the orderly trafficking of lipases and co-activators to specialized lipid droplet structures that are organized by specific lipid droplet scaffold proteins. Recent data indicates that protein perilipin A (Plin) is a lipid droplet scaffold protein that coordinates trafficking of lipolytic proteins in adipocytes. The proposed work seeks to build on these results and will characterize the exact temporal ordering of interactions among these lipolytic proteins during PKA stimulated lipolysis in adipocytes in vitro and in situ. Compared to fat cell lipolysis, very little is known about the organization of lipolysis in muscle;however, our preliminary data indicates that Mldp, a novel lipid droplet protein, organizes lipolysis in muscle for intracellular fatty acid oxidation. Using a panel of novel reagents and techniques, we propose to dissect lipolytic trafficking and lipolysis in model myocytes and in true muscle fibers. We anticipate that knowledge of the specific molecular interactions that control ectopic lipid clearance will allow us to devise screens for small molecules that promote this activity, with the long term goal of identifying lead compounds for treatment of obesity-related lipotoxicity.
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