Regulation of myocardial lipid and energy homeostasis

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DESCRIPTION (provided by applicant): Perturbations in energy and lipid homeostasis play a critical role in obesity and in the development of heart failure. The peroxisome proliferator-activated receptors (PPARs) have been implicated in the regulation of lipid metabolisms. However, the distinctive regulating mechanisms by each of PPAR subtypes remain unclear. Using the cardiomyocyte-restricted PPARdelta knockout mouse line (CR-PPARdelta-/-), we have demonstrated that PPARdelta plays a central role in maintaining basal myocardial fatty acid oxidation (FAO) and its absence in cardiomyocytes leads to cardiac dysfunction, myocardial lipid accumulation and lipotoxic cardiomyopathy. While PPARalpha and PPARdelta seemingly play overlapping roles in regulating myocardial FAO, it is not clear whether their co-existence is essential for the heart to maintain energy and lipid homeostasis. Our central hypothesis is that the coexistence of PPARalpha and delta is essential in maintaining myocardial energy and lipid homeostasis under normal and high-fat feeding conditions. Using the CR-PPARdelta-/-, a systemic PPARalpha-/- and an inducible, cardiomyocyte-restricted PPARdelta-/- approach, we will explore the following aims. Aim 1 will determine molecular mechanisms underpinning , cardiac phenotypic differences between the CR-PPARdelta-/- and the systemic PPARalpha-/- mice. Aim 2 will determine how PPARdelta regulates myocardial energy and lipid homeostasis in the absence of PPARalpha. We will assess myocardial lipid and energy homeostasis in a double knockout line of PPARdelta and alpha by crossing CR-PPARdelta-/- or an inducible CR-PPARdelta-/- line with the PPARalpha-/- line. Aim 3 will determine if PPARalpha is required to compensate for the loss of PPARalpha in the heart in high-fat feeding conditions. The potential defects in myocardial lipid and energy homeostasis, myocardial bioenergetics, as well as heart structure/function, will be studied in detail with methods of genetic and diet manipulations. Our overall objective is to understand how the heart maintains lipid homeostasis while deriving sufficient energy. The successful completion of the proposed studies will result in a better understanding of mechanisms underlying PPAR's role in regulating energy and lipid homeostasis in normal and obese states, leading to the identification of novel therapeutic targets for lipotoxicity found in many cardiac disorders.