Regulation of myocardial lipid and energy homeostasis

心肌脂质和能量稳态的调节

• 批准号: 7624429
• 负责人: QINGLIN YANG
• 金额: $ 35.5万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-01-15 至 2011-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7624429
• 关键词: Animal Model; Biochemistry; Bioenergetics; Cardiac; Cardiac Myocytes; Cardiomyopathies; Chronic; Condition; Data; Defect; Development; Diabetes Mellitus; Diet; Epidemic; Fasting; Fatty Acids; Fatty acid glycerol esters; Functional disorder; Gene Expression; Gene Targeting; Genes; Genetic; Goals; Heart; Heart Diseases; Heart failure; Homeostasis; Knock-out; Knockout Mice; Leptin; Ligands; Lipids; Mediating; Messenger RNA; Metabolic Pathway; Methods; Molecular; Mus; Myocardial; Myocardial dysfunction; Non-Insulin-Dependent Diabetes Mellitus; Obesity; PPAR alpha; PPAR delta; Patients; Peroxisome Proliferator-Activated Receptors; Play; Proteins; Public Health; Receptor Signaling; Regulation; Risk Factors; Role; Structure; Techniques; Testing; Transcript; United States; Up-Regulation; Work; Yang; activating transcription factor; diabetic; fatty acid metabolism; fatty acid oxidation; feeding; insight; lipid metabolism; mouse model; novel therapeutics; response; therapeutic target; uptake

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.

描述（由申请人提供）：能量和脂质稳态的扰动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）参与脂质代谢的调节。然而，每种 PPAR 亚型的独特调节机制仍不清楚。使用心肌细胞限制性PPARδ基因敲除小鼠系（CR-PPARδ-/-），我们证明PPARδ在维持基础心肌脂肪酸氧化（FAO）方面发挥着核心作用，心肌细胞中PPARδ的缺失会导致心脏功能障碍、心肌脂质积累和脂毒性心肌病。虽然 PPARα 和 PPARδ 在调节心肌脂肪酸方面似乎发挥着重叠的作用，但尚不清楚它们的共存是否对于心脏维持能量和脂质稳态至关重要。我们的中心假设是，PPARα 和 δ 的共存对于在正常和高脂肪喂养条件下维持心肌能量和脂质稳态至关重要。使用 CR-PPARdelta-/-、系统性 PPARalpha-/- 和诱导型心肌细胞限制性 PPARdelta-/- 方法，我们将探索以下目标。目标 1 将确定 CR-PPARδ-/- 和全身性 PPARα-/- 小鼠之间心脏表型差异的分子机制。目标 2 将确定在 PPARα 缺失的情况下 PPARδ 如何调节心肌能量和脂质稳态。我们将通过 CR-PPARdelta-/- 或诱导型 CR-PPARdelta-/- 系与 PPARalpha-/- 系交叉，评估 PPARδ 和 α 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 PPARα 来补偿高脂肪喂养条件下心脏中 PPARα 的损失。将通过遗传和饮食控制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质稳态。拟议研究的成功完成将有助于更好地了解 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。