Fatty acids comprise the most calorie-rich source of fuel for mammals. Fatty acids are taken up and stored in adipocytes and mobilized from this depot when needed by other tissues. Excess circulating fatty acids are a proximal cause of insulin resistance and type 2 diabetes, and therefore factors that modulate their cellular uptake and release have potentially direct connections with these pathological conditions. Proper fuel homeostasis requires that fatty acids move across the cell surface, the plasma membrane, rapidly and in large amounts. The adipocyte plasma membrane is particularly abundant in structures called caveolae, which are small membrane invaginations (""""""""little caves"""""""") enriched in cholesterol and sphingomyelin that are formed by the expression of caveolin-1 protein. Caveolae are a type of lipid raft characterized by resistance to dispruption by mild detergents such as fatty acids. Mice lacking caveolin-1 are insulin resistant and have abnormal fatty acid metabolism. We hypothesize that caveolin/caveolae in adipocytes play a role in the regulation of fatty acid movement across the plasma membrane and may mitigate their potentially pathological actions. A series of model cell lines have been created that express caveolin-1 to varying extents, resulting in the increased membrane cholesterol levels characteristic of lipid rafts such as caveolae in adipocyte. Preliminary data show that these cells are adipocyte-like in that they have enhanced acute fatty acid transmembrane uptake as well as enhanced fatty acid storage. Our two specific aims are 1. To determine the physiological and biochemical role of the novel caveolar protein, cavin, in caveolae function. We found that this protein undergoes stoichiometric ubiquitination, and we wish to determine the role of this unique modification in caveolae function and dynamics. 2. To study the effects of caveolar membrane lipid and protein composition on the rate and extent of fatty acid flux and storage. To this end, we will use a number of assays that allow real time monitoring of fatty acid transport rates in our extant cell lines, in adipocytes and in other model cell lines that we will create by transfection with proteins relevant to caveolae, transmembrane fatty acid flux and fatty acid storage. The long term goals of the application are understand the cellular compartmentalization of adipocytes as it applies to their role as the principle site of energy storage, and as sensors for the nutritional state of the organism, including homo sapiens. ? ? ?
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