Novel Role of Bscl2 in Cardiac Substrate Metabolism and Function

 说明（由申请人提供）心脏脂肪酸氧化（FAO）是成年哺乳动物心脏的主要能量来源。细胞内甘油三酯（TG）水解，释放脂肪酸（FA），产生收缩功能所需的ATP，在介导心脏底物代谢和功能中起着关键作用。心肌FAO和TG含量增加与肥胖和糖尿病患者的代谢性心肌病有关。但是脂肪代谢障碍中肥厚型心肌病的潜在机制仍然难以理解。同时，对控制心肌TG代谢和收缩功能的特定参与者知之甚少。BSCL 2基因突变导致人类2型贝拉尔迪内利-塞普先天性脂肪营养不良（BSCL 2）疾病。先前，我们已经产生了全局Bscl 2敲除（gKO）小鼠，其重现了具有脂肪营养不良和代谢紊乱的人BSCL 2。在这里，我们令人兴奋的初步数据显示，在Bscl 2 gKO小鼠心脏肥大，随后受损的收缩功能。特别是，心肌TG含量显着降低，而心脏FAO和糖原含量显着升高与全球或心脏特异性缺失（cKO）的Bscl 2的小鼠。此外，心肌Bscl 2的损失增加了心脏脂肪甘油三酯脂肪酶（ATGL）的蛋白质表达，ATGL是催化细胞内TG水解的初始和限速步骤的关键酶。这使我们假设Bscl 2调节心肌细胞中ATGL介导的甘油三酯周转和底物代谢，并且对心脏效率和功能至关重要。目的1将验证心肌Bscl 2缺失通过增加ATGL表达调节心脏甘油三酯周转和底物代谢的假设。我们将确定心肌基质代谢的缺陷与全球和心脏特异性损失的Bscl 2和解剖心肌Bscl 2损失和ATGL表达之间的机制联系的小鼠。目的2将检验Bscl 2在生理和病理条件下对心脏效率和功能是必需的这一假设。我们将研究是否过多的心脏FAO，独立于降低心脏TG含量，损害心脏效率，线粒体功能和能量，导致代谢性心肌病在非应激状态和脂肪代谢障碍。Bscl 2调节底物代谢在心脏生长和功能中的重要性将在血流动力学应激诱导的肥大模型中进一步检查。总之，这些目标将提供新的机制的见解肥厚型心肌病在完全脂肪代谢障碍，并揭示了一个重要的作用，ER膜蛋白（Bscl 2）在调节心肌能量代谢和功能，在正常和患病条件下。这些发现可能为代谢治疗心脏疾病提供新的治疗方法。

 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.