Regulation of myocardial lipid and energy homeostasis

描述(由申请者提供)：能量和脂质平衡的紊乱在肥胖和心力衰竭的发展中起着关键作用。过氧化物酶体增殖物激活受体(PPAR)参与了脂质代谢的调节。然而，每种PPAR亚型的不同调控机制仍不清楚。利用心肌细胞限制性PPARDelta基因敲除小鼠(CR-PPARDelta-/-)，我们证明了PPARDelta在维持基础心肌脂肪酸氧化(FAO)中起核心作用，心肌细胞中PPARDelta缺失会导致心功能不全、心肌脂质堆积和脂毒性心肌病。虽然PPARpha和PPARDelta似乎在调节心肌FAO方面扮演着重叠的角色，但尚不清楚它们的共存是否对心脏维持能量和脂质动态平衡至关重要。我们的中心假设是，在正常和高脂喂养条件下，PPARpha和Delta的共存对于维持心肌能量和脂质稳态是必不可少的。使用CR-PPAR Delta-/-，一种全身性PPARα/-和一种可诱导的，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-/-和全身性PPARα/-小鼠心脏表型差异的分子机制。目标2将确定在缺乏PPARpha的情况下，PPARDelta如何调节心肌能量和脂质稳态。我们将通过将CR-PPAR Delta-/-或一条可诱导的CR-PPAR Delta-/-线与PPARα-/-线杂交来评估PPARDelta和α双基因敲除线中的心肌脂质和能量动态平衡。目标3将确定是否需要PPARpha来补偿在高脂肪喂养条件下心脏中PPARpha的损失。将通过遗传和饮食调控的方法，详细研究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。我们的总体目标是了解心脏如何在获得足够能量的同时维持脂类平衡。这些拟议研究的成功完成将有助于更好地理解PPAR在调节正常和肥胖状态下的能量和脂质稳态方面的作用机制，从而识别出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.