Novel Role of Bscl2 in Cardiac Substrate Metabolism and Function

Bscl2 在心脏底物代谢和功能中的新作用

• 批准号: 9242050
• 负责人: Weiqin Chen
• 金额: $ 38万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2021-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9242050
• 关键词: Address; Adipocytes; Adipose tissue; Adult; Aging; BSCL2 gene; Bioenergetics; Cardiac; Cardiac Myocytes; Cardiomyopathies; Cessation of life; Clinical; Data; Defect; Development; Diabetes Mellitus; Disease; Endoplasmic Reticulum; Energy Metabolism; Energy-Generating Resources; Enzymes; Etiology; Experimental Animal Model; Familial generalized lipodystrophy; Fatty Acids; Functional disorder; Generations; Genes; Glucose; Glycogen; Goals; Growth; Heart; Heart Diseases; Heart Hypertrophy; Human; Hydrolysis; Hypertrophic Cardiomyopathy; Hypertrophy; Impairment; Knock-out; Knowledge; Label; Link; Lipase; Lipids; Lipodystrophy; Mediating; Membrane Proteins; Metabolic; Metabolic Diseases; Metabolism; Mitochondria; Modeling; Molecular; Mus; Mutation; Myocardial; Myocardial dysfunction; Neonatal; Obesity; Oxidative Stress; Oxygen Consumption; Pathogenesis; Pathologic; Patients; Physiological; Play; Process; Proteins; Role; Scheme; Stress; Structure; Testing; Therapeutic; Time; Triglycerides; Ubiquitination; constriction; fatty acid oxidation; glucose uptake; hemodynamics; insight; knock-down; lipid metabolism; novel; novel therapeutic intervention; overexpression; oxidation; premature; pressure; protein expression; public health relevance

 DESCRIPTION (provided by applicant) Cardiac fatty acid oxidation (FAO) is a major energy source for the adult mammalian heart. Intracellular triacylglyceride (TG) hydrolysis, which releases fatty acids (FAs) for the generation of ATP necessary for contractile function, plays a critical role in mediating cardiac substrate metabolism and function. Increased myocardial FAO and TG content have been associated with metabolic cardiomyopathy in obesity and diabetes. But mechanisms underlying hypertrophic cardiomyopathy in lipodystrophy remain elusive. Meanwhile, very little is known about the specific players that control myocardial TG metabolism and contractile function. Mutations at BSCL2 gene cause human type 2 Berardinelli-Seip Congenital Lipodystrophy (BSCL2) disease. Previously, we have generated global Bscl2 knockout (gKO) mice which recapitulate human BSCL2 with lipodystrophy and metabolic disorders. Here, our exciting preliminary data revealed cardiac hypertrophy with subsequently impaired contractile function in Bscl2 gKO mice. Especially, myocardial TG content was markedly reduced whereas cardiac FAO and glycogen content were substantially elevated in mice with global or cardiac-specific deletion (cKO) of Bscl2. Moreover, loss of myocardial Bscl2 increases the protein expression of cardiac adipose triglyceride lipase (ATGL), a critical enzyme that catalyzes the initial and rate-limiting step of intracellular TG hydrolysis. This leads us to hypothesize that Bscl2 regulates ATGL mediated triglyceride turnover and substrate metabolism in cardiomyocytes and is essential for cardiac efficiency and function. Aim 1 will test the hypothesis that myocardial Bscl2 deletion regulates cardiac triglyceride turnover and substrate metabolism by increasing ATGL expression. We will identify defects in myocardial substrate metabolism in mice with global and heart specific loss of Bscl2 and dissect the mechanistic links between myocardial Bscl2 loss and ATGL expression. Aim 2 will test the hypothesis that Bscl2 is essential for cardiac efficiency and function under physiological and pathological conditions. We will examine whether excessive cardiac FAO, independent of reduced cardiac TG content, impairs cardiac efficiency, mitochondrial function and energetics, leading to metabolic cardiomyopathy in unstressed states and lipodystrophy. The importance of Bscl2 regulated substrate metabolism in cardiac growth and function will be further examined in hemodynamic stress induced hypertrophic model. Together, these aims will provide novel mechanistic insights into the hypertrophic cardiomyopathy in complete lipodystrophy and uncover an essential role of an ER membrane protein (Bscl2) in regulating myocardial energy metabolism and function under normal and diseased conditions. These findings could provide new therapeutic approaches in metabolically treating cardiac disorders.

 描述（由适用的）心脏脂肪酸氧化（FAO）是成年哺乳动物心脏的主要能源。细胞内三酰基甘油三酸酯（TG）水解，该水解释放脂肪酸（FAS）以生成收缩功能所需的ATP，在介导心脏底物代谢和功能中起着至关重要的作用。心肌粮农组织和TG含量增加与肥胖症和糖尿病的代谢性心肌病有关。但是脂肪营养不良中肥厚性心肌病的基础机制仍然难以捉摸。同时，对于控制心肌TG代谢和收缩功能的特定玩家知之甚少。 BSCL2基因的突变导致人类2型Berardinelli-Seip先天性脂肪营养不良（BSCL2）疾病。以前，我们已经产生了全球BSCL2敲除（GKO）小鼠，该小鼠用脂肪营养不良和代谢性疾病概括了人BSCL2。在这里，我们令人兴奋的初步数据揭示了心脏肥大，随后BSCL2 GKO小鼠的收缩功能受损。特别是，在BSCL2的全球或心脏特异性缺失（CKO）的小鼠中，心肌TG含量显着降低，而心脏粮农组织和糖原含量显着升高。此外，心肌BSCL2的丧失增加了心脏脂肪甘油三酸酯脂肪酶（ATGL）的蛋白质表达，这是一种临界酶，可催化细胞内TG水解的初始和限制步骤。这使我们假设BSCL2调节心肌细胞中ATGL介导的甘油三酸酯的周转和底物代谢，并且对于心脏效率和功能至关重要。 AIM 1将检验以下假设：心肌BSCL2缺失通过增加ATGL表达来调节心脏甘油三酸酯的周转和底物代谢。我们将确定具有BSCL2全球和心脏特异性损失的小鼠心肌底物代谢缺陷，并剖析心肌BSCL2损失和ATGL表达之间的机械联系。 AIM 2将检验以下假设：BSCL2对于身体和病理条件下的心脏效率和功能至关重要。我们将检查过多的心脏粮农组织，独立于降低心脏TG含量，损害心脏效率，线粒体功能和能量学，导致无压力状态和脂肪营养不良的代谢性心肌病。 BSCL2调节底物代谢在心脏生长和功能中的重要性将在血液动力学诱导的肥厚模型中进一步研究。共同，这些目标将为完全脂肪营养不良的肥厚性心肌病提供新的机械见解，并发现ER膜蛋白（BSCL2）在调节的心肌能量代谢和正常条件下的功能中的重要作用。这些发现可以在代谢治疗心脏病中提供新的治疗方法。