Cardiovascular disease is, on average, the leading cause of death worldwide. Obesity is a related threat to human health which has reached epidemic proportions globally. The heparan sulfate proteoglycan (HSPG) syndecan-4 affects lipid metabolism at the intersection between both of these health concerns. Syndecan-4 is a ubiquitous molecule found at the surfaces of most animal cells. The high structural heterogeneity of HSPGs facilitates their interaction with a variety of molecules, including several involved in lipid metabolism. Additionally, syndecan-4 has been implicated in cell growth signaling and the differentiation and growth of fat cells. Further basic science research in the specific role of syndecan-4 in lipid metabolism is crucial in order to provide a framework for understanding the role it may play in atherogenesis and obesity, and in identifying molecular targets for treatment. I hypothesize that loss of syndecan-4 function should alter lipid metabolism and adipogenesis. I propose to investigate changes in plasma and tissue lipid levels and other markers of lipid metabolism in normal and syndecan-4 knockout mouse models with normal and high-fat diets. Levels of all other major cell-surface HSPGs will be measured in knockout mouse tissues to determine any cross-regulatory effects associated with the impairment of syndecan-4 function. Effects on adipogenesis will be studied in cultured differentiating preadipocytes with syndecan-4 mRNA """"""""knocked down"""""""" via RNA interference methods. Finally, proteomics analysis will be performed to determine binding partners of syndecan-4 during the preadipocyte-adipocyte transition.
