EXCEED THE SPACE PROVIDED. This renewal request funds to continue investigations of the regulation of lipoprotein lipase (LpL). During Ithe current funding period of this award, we studied the roles of the VLDL receptor in LpL transfer to the lendothelial surface, investigated the role of heparin binding in LpL localization and stability, and created lanimals expressing hinged tandem repeat LpL dimers in muscle. We created a novel model of lipotoxicity Iby expression of an anchored LpL transgene in cardiomyocytes. In addition, we floxed the LpL gene and lproduced heart-specific LpL knockout mice. Our studies suggest that LpL has distinct actions on lendothelial and parenchymal cells that modulate different steps in tissue lipid acquisition. During the continuation of this project, we propose to use genetically altered mice to dissect the roles of endothelial cell and cardiomyocyte associated LpL. This will be done by creating animals that only contain LpL on the cardiomyocyte or the endothelial surface. In addition, we will study the importance of LpL dissociation from endothelial cells by producing mice with LpL anchored to the endothelium. The specfic aims of this renewal are as follows:
Aim 1. To assess the physiological role of cardiomyocyte associated LpL on cardiac lipid uptake in hearts not expressing normal LpL. Mice containing myocyte anchored, but not endothelial cell associated, LpL will be produced.
Aim 2. To determine the effects of LpL overexpression in endothelial cells on plasma lipoproteins and tissue lipid uptake. An LpL minigene driven by the TIE2 promoter-enhancer will be used to create a new transgenic mouse line.
Aim 3. To determine the importance of LpL release as a method to protect tissues from overexposure to lipoprotein-derived fatty acids. Transgenic mice with LpL anchored to endothelial cells will be produced and LpL activity and actions in these animals will be assessed. The proposed experiments will, we expect, define two pathways for lipid delivery to cells, endothelial LpL generation of free fatty acids and parencymal cell surface LpL mediated uptake of core lipids, and will provide fundamental information on lipid delivery to tissues. PERFORMANCE SITE ========================================Section End===========================================
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| Drosatos, Konstantinos; Lymperopoulos, Anastasios; Kennel, Peter Johannes et al. (2015) Pathophysiology of sepsis-related cardiac dysfunction: driven by inflammation, energy mismanagement, or both? Curr Heart Fail Rep 12:130-40 |
| Willecke, Florian; Scerbo, Diego; Nagareddy, Prabhakara et al. (2015) Lipolysis, and not hepatic lipogenesis, is the primary modulator of triglyceride levels in streptozotocin-induced diabetic mice. Arterioscler Thromb Vasc Biol 35:102-10 |
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