Novel Role of Bscl2 in Cardiac Substrate Metabolism and Function

 说明(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。甘油三酯(TG)在细胞内的水解，释放脂肪酸(FAs)，产生收缩功能所需的ATP，在调节心脏底物代谢和功能方面起着关键作用。肥胖和糖尿病患者心肌FAO和TG含量升高与代谢性心肌病有关。但脂肪营养不良所致肥厚型心肌病的发病机制仍不清楚。同时，对控制心肌甘油三酯代谢和收缩功能的特定因子知之甚少。BSCL2基因突变导致人类2型Berardinelli-Seip先天性脂肪营养不良症(BSCL2)。以前，我们已经产生了全球Bscl2基因敲除(GKO)小鼠，它们重现了患有脂肪营养不良和代谢紊乱的人类BSCL2。在这里，我们令人兴奋的初步数据显示，Bscl2 GKO小鼠心肌肥大，随后收缩功能受损。尤其是Bscl2基因整体缺失或心脏特异性缺失(CKO)的小鼠，心肌甘油三酯含量显著降低，而心脏FAO和糖原含量显著升高。此外，心肌Bscl2的缺失增加了心脏脂肪甘油三酯脂肪酶(ATGL)的蛋白表达，ATGL是催化细胞内甘油三酯水解的起始和限速步骤的关键酶。这导致我们假设Bscl2调节ATGL介导的甘油三酯在心肌细胞中的代谢和底物代谢，对心脏的效率和功能是必不可少的。目的1验证心肌Bscl2缺失通过增加ATGL表达来调节心脏甘油三酯代谢和底物代谢的假说。我们将在Bscl2的整体缺失和心脏特异性缺失的小鼠中识别心肌底物代谢的缺陷，并剖析心肌Bscl2缺失与ATGL表达之间的机制联系。目的2验证Bscl2在生理和病理条件下对心脏效率和功能起重要作用的假设。我们将研究过量的心脏FAO是否会损害心脏效率、线粒体功能和能量，从而导致非应激状态下的代谢性心肌病和脂肪营养不良。Bscl2调节的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厚模型中进一步研究。总之，这些目标将为完全性脂营养不良的肥厚性心肌病提供新的机制见解，并揭示ER膜蛋白(Bscl2)在正常和疾病条件下调节心肌能量代谢和功能的重要作用。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.