Regulation of myocardial lipid and energy homeostasis

描述（由申请人提供）：能量和脂质稳态的紊乱在肥胖和心力衰竭的发展中起关键作用。过氧化物酶体增殖物激活受体（PPARs）参与脂质代谢的调节。然而，各亚型的不同调节机制仍不清楚。使用心肌细胞限制性PPARdelta敲除小鼠系（CR-PPARdelta-/-），我们已经证明PPARdelta在维持基础心肌脂肪酸氧化（FAO）中起核心作用，并且其在心肌细胞中的缺失导致心功能障碍、心肌脂质积聚和脂毒性心肌病。虽然PPARalpha和PPARdelta似乎在调节心肌FAO中发挥重叠的作用，但尚不清楚它们的共存是否对心脏维持能量和脂质稳态至关重要。我们的中心假设是，在正常和高脂喂养条件下，PPARalpha和delta的共存对维持心肌能量和脂质稳态至关重要。使用CR-PPARdelta-/-、系统性PPARalpha-/-和诱导性心肌细胞限制性PPARdelta-/-方法，我们将探索以下目标。目的1将确定CR-PPARdelta-/-和全身PPARalpha-/-小鼠之间心脏表型差异的分子机制。目的2将确定在没有PPARalpha的情况下，PPARdelta如何调节心肌能量和脂质稳态。我们将通过交叉CR-PPARdelta-/-或诱导型CR-PPARdelta-/-系与PPARalpha-/-系来评估PPARdelta和alpha双敲除系中的心肌脂质和能量稳态。目标3将确定是否需要PPARalpha来补偿高脂喂养条件下心脏中PPARalpha的损失。心肌脂质和能量稳态，心肌生物能量学，以及心脏结构/功能的潜在缺陷，将详细研究与遗传和饮食操纵的方法。我们的总体目标是了解心脏如何维持脂质稳态，同时获得足够的能量。拟议研究的成功完成将使人们更好地了解PPAR在正常和肥胖状态下调节能量和脂质稳态的作用机制，从而确定许多心脏疾病中发现的脂毒性的新治疗靶点。

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.