Sigmar1 in lipid metabolism

Sigmar1 在脂质代谢中的作用

基本信息

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
项目类别：
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

项目摘要

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.

肥胖与不同器官中脂质（脂肪变性）的依托沉积有关，包括胰腺，肾脏，血管，肝脏，骨骼肌和心脏。过量毒性脂质物种的积累会改变细胞信号，促进线粒体功能障碍并增加所有这些器官的细胞死亡。我们对揭示了代谢中Sigma-1受体（SIGMAR1）蛋白的分子功能感兴趣，因为据报道它与含脂质的微域有关，这表明在代谢疾病的病理生理学中具有潜在的作用。我们发现Sigmar1在心脏中明确表达，其中脂肪酸氧化（FAO）是主要能量来源（约70％）。该建议的初步数据确定SIGMAR1的组织内部功能是正常生理条件下脂质代谢的必要调节剂，并且响应饮食诱导的肥胖胁迫。 SIGMAR1全局敲除小鼠的心脏表明甘油三酸酯的水平增加，脂质液滴的积累以及线粒体呼吸的抑制，这表明SIGMAR1在脂质代谢中的潜在功能。为了阐明在物理和病理生理条件下SigMAR1的分子功能，我的实验室最近生成了心脏特异性的Sigmar1转基因小鼠，用于过表达和心脏特异性SIGMAR1条件敲除小鼠模型。该提案的中心假设是脂质代谢的SIGMAR1依赖性激活受到保护，以防止代谢应激诱导的心脏功能障碍和病理重塑。 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 regulatory 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通过线粒体脂肪酸（FA）摄取和氧化。我们将使用综合的分子，遗传和功能方法与遗传改性小鼠一起确定直接参与并定义Sigmar1在脂质代谢中的作用的分子机制。线粒体粮农组织并发现了DIO中细胞保护的新型分子机制。

项目成果

期刊论文数量（15）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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
作者：
通讯作者：

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。

DOI：
发表时间：
2022
期刊：
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
影响因子：
0
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

Sigmar1's Molecular, Cellular, and Biological Functions in Regulating Cellular Pathophysiology.