Sigmar1 in lipid metabolism

肥胖与不同器官的脂质异位沉积（脂肪变性）有关，包括胰腺、肾脏、血管、肝脏、骨骼肌和心脏。过量有毒脂质的积累改变了细胞信号，促进了线粒体功能障碍，增加了所有这些器官的细胞死亡。我们开始对Sigma-1受体（Sigmar1）蛋白在代谢中的分子功能感兴趣，因为有报道称它与含脂微结构域相关，这表明它在代谢疾病的病理生理学中具有潜在作用。我们发现Sigmar1在心脏中大量表达，其中脂肪酸氧化（FAO）是主要的能量来源（约70%）。本研究的初步数据表明，在正常生理条件下，Sigmar1的组织内在功能是脂质代谢的重要调节因子，并对饮食引起的肥胖应激做出反应。Sigmar1基因全基因敲除小鼠的心脏表现出甘油三酯水平升高、脂滴积聚和线粒体呼吸抑制，这表明Sigmar1在脂质代谢中的潜在功能。为了阐明Sigmar1在生理和病理生理条件下的分子功能，我的实验室最近建立了心脏特异性Sigmar1转基因小鼠过表达模型和心脏特异性Sigmar1条件敲除小鼠模型。该建议的中心假设是sigmar1依赖性的脂质代谢激活对代谢应激诱导的心功能障碍和病理性重构具有保护作用。在强有力的初步数据的指导下，这一假设将通过追求3个特定目标来验证：i) Aim 1将确定Sigmar1在调节脂质代谢中的新功能，ii) Aim 2将确定Sigmar1在饮食诱导肥胖（DIO）小鼠模型中代谢应激中的作用，以及iii) Aim 3将确定Sigmar1通过线粒体脂肪酸（FA）摄取和氧化在脂质代谢中的功能的分子机制。我们将使用综合的分子、遗传和功能方法，结合转基因小鼠来确定Sigmar1在脂质代谢中的作用的直接参与和分子机制。本项目将确定一种新的治疗靶点来调节线粒体FAO，并发现DIO细胞保护的一种新的分子机制。

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.