The role of LPCAT3 in pathogenesis of diabetic cardiomyopathy

LPCAT3在糖尿病心肌病发病机制中的作用

• 批准号: 10867671
• 负责人: Tomasz Krzysztof Bednarski
• 金额: $ 15.27万
• 依托单位: UNIVERSITY OF NEBRASKA LINCOLN
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10867671
• 关键词: ATF6 gene; Acute; Acyltransferase; Affect; Age; Animal Experiments; Animals; Antibodies; Apoptosis; Area; Biological Assay; Blood; Body Composition; Body Weight; C57BL/6 Mouse; CD36 gene; Cardiac; Cardiac Myocytes; Cardiovascular Diseases; Caspase; Cause of Death; Caymans; Cd68; Cell Line; Cell Proliferation; Cell Survival; Cells; Ceramides; Chemicals; Cholesterol; Cholesterol Esters; Collaborations; Computer software; Contracts; Control Groups; Custom; Cytomegalovirus; Dependovirus; Development; Diabetes Mellitus; Diet; Diet Research; Diglycerides; Disease; Dose; Dyslipidemias; Eating; Ensure; Enzymes; Evaluation; Fasting; Fat-Restricted Diet; Fatty acid glycerol esters; Felis catus; Future; GCG gene; GRP78 gene; GRP94; Gene Expression; Genotype; Genus Hippocampus; Glucose; Glucose tolerance test; Glutamine; Glycolysis; Heart Abnormalities; Heart failure; High Fat Diet; Hour; Hypertension; ITGAM gene; Image; Incubated; Individual; Inflammation; Injections; Insulin; Insulin Resistance; Interleukin-4; Interleukin-6; Intraperitoneal Injections; Knock-out; Knockout Mice; Knowledge; Laboratories; Lecithin; Lipid Peroxidation; Lipids; Lipolysis; Liver; Liver X Receptor; LoxP-flanked allele; Lysophosphatidylcholines; Mass Fragmentography; Measures; Membrane; Metabolic; Metabolic Diseases; Metabolic Pathway; Metabolism; Microscope; Mitochondria; Molecular; Monitor; Mus; Myocardial dysfunction; Myosin Heavy Chains; Nebraska; Non-Insulin-Dependent Diabetes Mellitus; Nonesterified Fatty Acids; Obese Mice; Obesity; Oils; Oxidative Phosphorylation; Oxidative Stress; Oxygen Consumption; Palmitates; Pancreas; Pathogenesis; Patients; Pharmacotherapy; Phenotype; Phospholipids; Phosphorylation; Physiology; Plasma; Play; Polyunsaturated Fatty Acids; Positioning Attribute; Prevention strategy; Production; Promega; Proteins; RNA Splicing; Reactive Oxygen Species; Receptor Activation; Respiration; Risk Factors; Role; SOD2 gene; Signal Transduction; Stains; Streptozocin; Structure; Supplementation; System; TNF gene; Testing; The Jackson Laboratory; Thiobarbituric Acid Reactive Substances; Tissues; Tobacco use; Transforming Growth Factor alpha; Universities; Unsaturated Fatty Acids; Ventricular Cardiac alpha-Myosin; Western Blotting; Woman; XBP1 gene; alpha Actinin; continuous cell line; db/db mouse; diabetic; diabetic cardiomyopathy; diagnostic tool; dietary; digital; endoplasmic reticulum stress; experimental group; experimental study; extracellular; fatty acid oxidation; feeding; heart function; heart metabolism; improved; in vivo; insulin sensitivity; lipid biosynthesis; lipidome; long chain fatty acid; male; men; nano-string; obesity prevention; overexpression; oxidation; oxidative DNA damage; prevent; standard measure; superoxide dismutase 1; transcription factor; transduction efficiency

Cardiovascular diseases are the number one cause of death globally. Most CVDs are caused by risk factors such as tobacco use, hypertension, obesity or diabetes. Diabetic cardiomyopathy (DC) is characterized by abnormal cardiac structure and function in the absence of other cardiac risk factors and is often undiagnosed in patients with diabetes mellitus. Untreated, this condition increases the chance of heart failure at least 2.4-fold in men and 5.1-fold in women compared to individuals without diabetes. Despite the increase in the number of cases in the past several decades, the underlying molecular mechanisms of DC pathogenesis remain poorly understood, thereby preventing the development of effective diagnostic tools and pharmacotherapies as well as preventive strategies. One of the emerging hypothesis is that altered membrane polyunsaturated fatty acid composition can activate ER stress signaling, oxidative stress and inflammation in cells. It has been speculated that increased membrane phospholipid saturation may be an underlying cause of many metabolic disorders. Lysophosphatidylcholine acyltransferase 3 (LPCAT3) is a major cardiac enzyme that catalyzes the formation of phosphatidylcholine (PC) from lysophosphatidylcholine. LPCAT3 preferentially synthesizes PC containing unsaturated fatty acids at the sn-2 position. A recent study has shown that LPCAT3 overexpression in livers of obese diabetic db/db mice effectively reduced ER stress by modulating PC saturation. However, the role of LPCAT3 in cardiac metabolism is very poorly understood. Therefore, the proposed project aims at establishing the role of LPCAT3 in cardiac function and investigating the effect that LPCAT3 deficiency may play in development of DC. Additionally, the project will investigate the potential of PC supplemented diet to improve cardiac function in obese mice. Finally, the proposed study will investigate the potential of LPCAT3 overexpression through its transcription factor - liver X receptor (LXR) activation on improving cardiomyocyte structure and function in acute lipotoxicity.

心血管疾病是全球头号死亡原因。大多数心血管疾病是由风险引起的 吸烟、高血压、肥胖或糖尿病等因素。糖尿病性心肌病（DC） 特征为在没有其他心脏危险因素的情况下心脏结构和功能异常， 在糖尿病患者中经常未被诊断。如果不治疗，这种情况会增加 与无糖尿病的个体相比，男性心力衰竭至少为2.4倍，女性为5.1倍。 尽管在过去几十年中病例数量有所增加，但潜在的分子 DC发病机制仍然知之甚少，从而阻止了DC的发展。 有效的诊断工具和药物治疗以及预防战略。一体的新兴 假设改变膜多不饱和脂肪酸组成可以激活ER应激 细胞中的信号传导、氧化应激和炎症。据推测，增加的膜 磷脂饱和可能是许多代谢紊乱的根本原因。 溶血磷脂酰胆碱酰基转移酶3（LPCAT 3）是一种主要的心脏酶，催化 由溶血磷脂酰胆碱形成磷脂酰胆碱（PC）。LPCAT 3优先合成 在sn-2位含有不饱和脂肪酸的PC。最近的一项研究表明，LPCAT 3 肥胖糖尿病db/db小鼠肝脏中的过表达通过调节PC有效地降低ER应激 饱和度然而，LPCAT 3在心脏代谢中的作用知之甚少。因此 拟议的项目旨在确定LPCAT 3在心脏功能中的作用，并研究其对心脏功能的影响。 LPCAT 3缺陷可能在DC的发展中起作用。此外，该项目将调查 PC补充饮食改善肥胖小鼠心脏功能的潜力。最后，研究建议 将研究LPCAT 3通过其转录因子-肝脏X受体过度表达的可能性 (LXR)激活改善急性脂毒性心肌细胞结构和功能。