Sigmar1 in lipid metabolism

肥胖与不同器官中脂质的异位沉积（脂肪变性）相关，所述器官包括胰腺、肾脏、血管、肝脏、骨骼肌和心脏。过量有毒脂质物质的积累改变了细胞信号传导，促进了线粒体功能障碍，并增加了所有这些器官中的细胞死亡。我们开始对揭示Sigma-1受体（Sigmar 1）蛋白在代谢中的分子功能感兴趣，因为据报道它与含脂质的微结构域相关，这表明在代谢疾病的病理生理学中具有潜在作用。我们发现Sigmar 1在心脏中大量表达，其中脂肪酸氧化（FAO）是能量的主要来源（约70%）。对该提议至关重要的初步数据鉴定了Sigmar 1的组织内在功能，其是在正常生理条件下和响应于饮食诱导的肥胖应激的脂质代谢的必要调节剂。来自Sigmar 1全基因敲除小鼠的心脏显示甘油三酯水平增加、脂滴积聚和线粒体呼吸抑制，表明Sigmar 1在脂质代谢中的潜在功能。为了阐明Sigmar 1在生理和病理生理条件下的分子功能，本实验室最近建立了心脏特异性Sigmar 1过表达转基因小鼠和心脏特异性Sigmar 1条件性敲除小鼠模型。该建议的中心假设是Sigmar 1依赖性的脂质代谢活化对代谢应激诱导的心功能不全和病理性重塑具有保护作用。在强有力的初步数据的指导下，将通过追求3个具体目标来检验这一假设：i）目的1将确定Sigmar 1在调节脂质代谢中的新功能，ii）目的2将确定Sigmar 1在饮食诱导的肥胖症（DIO）小鼠模型中的代谢应激中的作用，目的3通过线粒体脂肪酸（FA）摄取和氧化来确定Sigmar 1在脂质代谢中的分子机制。我们将使用整合的分子，遗传和功能的方法，结合转基因小鼠，以确定直接参与和定义Sigmar 1的脂质代谢中的作用的分子机制。该项目将确定一个新的治疗靶点来调节线粒体FAO，并发现DIO中细胞保护的新分子机制。

Obesity is associated with ectopic deposition of lipid (steatosis) in different organs including pancreas, kidneys, blood vessels, liver, skeletal muscle, and heart. The accumulation of excessive toxic lipid species alters cellular signaling, promote mitochondrial dysfunction and increase cellular death in all these organs. We became interested in uncovering the molecular function of Sigma-1 receptor (Sigmar1) proteins in metabolism as it was reported to be associated with lipid-containing micro-domains suggesting a potential role in the pathophysiology of metabolic diseases. We found that Sigmar1 is abundantly expressed in the heart, where fatty acid oxidation (FAO) serves as the primary source of energy (approximately 70%). Preliminary data central to this proposal identify tissue-intrinsic function of Sigmar1 as an essential regulator of lipid metabolism under the normal physiological condition and in response to diet induced obesity stress. Hearts from Sigmar1 global knockout mouse demonstrate an increased level of triglycerides, accumulation of lipid droplets and suppression of mitochondrial respiration suggesting a potential function of Sigmar1 in lipid metabolism. To elucidate the molecular function of Sigmar1 under physiological and pathophysiological conditions, my laboratory recently generated cardiac-specific Sigmar1 transgenic mouse for overexpression and cardiac-specific Sigmar1 conditional knockout mouse models. The central hypothesis of this proposal is Sigmar1-dependent activation of lipid metabolism is protective against metabolic stress-induced cardiac dysfunction and pathological remodeling. Guided by strong preliminary data, this hypothesis will be tested by pursuing 3 specific aims: i) Aim 1 will determine a novel function for Sigmar1 in regulating lipid metabolism, ii) Aim 2 will determine the role of Sigmar1 in metabolic stress in mouse model of diet-induced obesity (DIO), and iii) Aim 3 will determine the molecular mechanism of Sigmar1’s function in lipid metabolism through mitochondrial fatty acid (FA) uptake and oxidation. We will use integrated molecular, genetic, and functional approaches in conjunction with genetically modified mice to determine the direct involvement and define the molecular mechanisms of Sigmar1’s role in lipid metabolism. This proposed project will identify a novel therapeutic target to regulate mitochondrial FAO and discover a novel molecular mechanism of cellular protection in DIO.