Sigmar1 in lipid metabolism

Sigmar1 在脂质代谢中的作用

• 批准号: 10534192
• 负责人: Md. Shenuarin Bhuiyan
• 金额: $ 36.5万
• 依托单位: LOUISIANA STATE UNIV HSC SHREVEPORT
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-12-15 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10534192
• 关键词: Acute; Adult; Affect; Binding; Biochemical; Blood Vessels; Cardiac; Cardiac Myocytes; Cessation of life; Characteristics; Chronic; Data; Defect; Deposition; Diabetes Mellitus; Energy-Generating Resources; Exhibits; Fasting; Fatty Acids; Functional disorder; Genetic; Goals; Heart; Heart Diseases; High Fat Diet; In Vitro; Infection; Kidney; Knockout Mice; Laboratories; Length; Lipids; Liver; Mediating; Metabolic; Metabolic Diseases; Metabolic dysfunction; Metabolic stress; Metabolism; Mitochondria; Modeling; Molecular; Morphology; Mus; Mutate; Myocardial; Myocardial dysfunction; Myocardium; Neonatal; Nonesterified Fatty Acids; Obesity; Organ; Pancreas; Pathologic; Pathology; Pathway interactions; Physiological; Regulation; Reporting; Respiration; Role; Shapes; Signal Transduction; Skeletal Muscle; Small Interfering RNA; Stress; Stress Tests; Testing; Tissues; Transgenic Mice; Transgenic Organisms; Triglycerides; Ventricular Remodeling; adenoviral mediated; cardiovascular risk factor; conditional knockout; diet-induced obesity; fatty acid oxidation; feeding; genetic approach; in vivo; interest; knock-down; lipid metabolism; lipid transport; long chain fatty acid; mitochondrial dysfunction; mouse model; new therapeutic target; novel; overexpression; oxidation; prevent; receptor; receptor expression; receptor function; response; sigma-1 receptor; therapeutic target; uptake

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.

肥胖与不同器官中的脂质异位沉积（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会改变细胞信号传导，促进线粒体功能障碍并增加所有这些器官的细胞死亡。我们对揭示 Sigma-1 受体 (Sigmar1) 蛋白在代谢中的分子功能产生了兴趣，因为据报道它与含脂质微结构域相关，表明其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，脂肪酸氧化 (FAO) 是心脏的主要能量来源（约 70%）。该提案的核心初步数据确定了 Sigmar1 的组织内在功能，作为正常生理条件下脂质代谢的重要调节剂，并响应饮食引起的肥胖应激。 Sigmar1 全基因敲除小鼠的心脏显示出甘油三酯水平升高、脂滴积累和线粒体呼吸抑制，表明 Sigmar1 在脂质代谢中具有潜在功能。为了阐明 Sigmar1 在生理和病理生理条件下的分子功能，我的实验室最近生成了心脏特异性 Sigmar1 转基因小鼠过度表达和心脏特异性 Sigmar1 条件敲除小鼠模型。该提议的中心假设是 Sigmar1 依赖性脂质代谢激活可预防代谢应激引起的心脏功能障碍和病理重塑。在强有力的初步数据指导下，该假设将通过追求 3 个具体目标进行检验：i) 目标 1 将确定 Sigmar1 在调节脂质代谢中的新功能，ii) 目标 2 将确定 Sigmar1 在饮食诱导肥胖 (DIO) 小鼠模型代谢应激中的作用，以及 iii) 目标 3 将确定 Sigmar1 在脂质代谢中功能的分子机制 通过线粒体脂肪酸（FA）的摄取和氧化。我们将结合转基因小鼠使用综合分子、遗传和功能方法来确定 Sigmar1 在脂质代谢中的直接参与并定义其作用的分子机制。该拟议项目将确定调节线粒体FAO的新治疗靶点，并发现DIO中细胞保护的新分子机制。

项目成果

Kv1.1 potassium channel subunit deficiency alters ventricular arrhythmia susceptibility, contractility, and repolarization.

• DOI: 10.14814/phy2.14702
• 发表时间: 2021-01
• 期刊: Physiological reports
• 影响因子: 2.5
• 作者: Trosclair K;Si M;Watts M;Gautier NM;Voigt N;Traylor J;Bitay M;Baczko I;Dobrev D;Hamilton KA;Bhuiyan MS;Dominic P;Glasscock E
• 通讯作者: Glasscock E

The ATX-LPA Axis Regulates Vascular Permeability during Cerebral Ischemic-Reperfusion.

• DOI: 10.3390/ijms23084138
• 发表时间: 2022-04-08
• 期刊: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
• 影响因子: 5.6
• 作者: Bhattarai, Susmita;Sharma, Sudha;Subedi, Utsab;Ara, Hosne;Shum, Alika;Milena, Murov;Bhuiyan, Md Shenuarin;Kidambi, Srivatsan;Sun, Hong;Miriyala, Sumitra;Panchatcharam, Manikandan
• 通讯作者: Panchatcharam, Manikandan

Alteration of Cellular Energy Metabolism through LPAR2-Axin2 Axis in Gastric Cancer.

• DOI: 10.3390/biom12121805
• 发表时间: 2022-12-02
• 期刊: Biomolecules
• 影响因子: 5.5

Sigmar1 Deficiency Results in Pulmonary Fibrosis Associated with Increased Pulmonary Inflammation and Surfactant Protein Levels in Mice Lung.

Sigmar1 缺乏会导致肺纤维化，并与小鼠肺部炎症和表面活性剂蛋白水平增加相关。

• 发表时间: 2022
• 期刊: FASEB journal : official publication of the Federation of American Societies for Experimental Biology
• 作者: Remex,NazninS;Abdullah,ChowdhuryS;Aishwarya,Richa;Morshed,MohammedM;Nitu,Sadia;Traylor,James;Hartman,Brandon;King,Judy;Kevil,Christopher;Orr,AnthonyW;Bhuiyan,MdS
• 通讯作者: Bhuiyan,MdS

Stimulant Drugs of Abuse and Cardiac Arrhythmias.

• DOI: 10.1161/circep.121.010273
• 发表时间: 2022-01
• 期刊: Circulation. Arrhythmia and electrophysiology
• 作者: Dominic P;Ahmad J;Awwab H;Bhuiyan MS;Kevil CG;Goeders NE;Murnane KS;Patterson JC;Sandau KE;Gopinathannair R;Olshansky B
• 通讯作者: Olshansky B