Obesity is a health problem that is reaching epidemic proportions in the United States and has become a major and growing factor contributing to an increased prevalence of Type II diabetes and an increased risk of premature death from cardiovascular disease. Despite the need for therapeutic options to control obesity, little is known about the intracellular mechanisms that regulate fat storage and release in adipose tissue. Fatty acids, the body's major energy currency, are stored as triacylglycerols in large intracellular lipid droplets in adipocytes. The perilipins are the most abundant proteins on the surfaces of lipid droplets in adipocytes and are also found in steroidogenic cells. The proposed studies test the hypotheses that 1) perilipins facilitate triacylglycerol storage by forming a protective barrier against cytosolic lipases, and 2) phosphorylation of perilipins facilitates lipolysis in lipolytically stimulated adipocytes by attenuating the barrier to facilitate lipase access to stored triacylglycerols.
The Specific Aims of the proposed research are to 1) define the structural domains of perilipin A required for its targeting to and embedding into lipid droplets, 2) to study how perilipin A protects stored triacylglycerols from hormone-sensitive lipase, and 3) to elucidate the role of the phosphorylation of perilipin A in the promotion of lipolysis.
These aims will be tested by the expression of intact and mutant perilipin A in cultured cells that lack perilipins followed by assays for lipid storage and release, and the presence of the mutant perilipins on lipid droplets.
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