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

基本信息

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
项目类别：
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

项目摘要

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.

心血管疾病是全球第一大死亡原因。大多数CVD是由风险引起的吸烟、高血压、肥胖或糖尿病等因素。糖尿病心肌病（DC）是其特征是在没有其他心脏危险因素的情况下心脏结构和功能异常，并且糖尿病患者常常无法确诊。如果不进行治疗，这种情况会增加以下风险：与未患糖尿病的人相比，男性心力衰竭的发生率至少高 2.4 倍，女性心力衰竭的发生率至少高 5.1 倍。尽管过去几十年来病例数量有所增加，但潜在的分子机制 DC 发病机制仍知之甚少，从而阻碍了 DC 的发展有效的诊断工具和药物治疗以及预防策略。新兴的之一假设改变膜多不饱和脂肪酸成分可以激活内质网应激细胞内的信号传导、氧化应激和炎症。据推测，增加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 (LPCAT3) 是一种主要的心肌酶，可催化从溶血磷脂酰胆碱形成磷脂酰胆碱（PC）。 LPCAT3优先合成 PC的sn-2位含有不饱和脂肪酸。最近的一项研究表明 LPCAT3 肥胖糖尿病 db/db 小鼠肝脏中的过度表达通过调节 PC 有效降低 ER 应激饱和。然而，人们对 LPCAT3 在心脏代谢中的作用知之甚少。因此，拟议项目旨在确定 LPCAT3 在心脏功能中的作用并研究其影响 LPCAT3 缺陷可能在 DC 的发展中发挥作用。此外，该项目还将调查 PC补充饮食改善肥胖小鼠心脏功能的潜力。最后，提出的研究将研究 LPCAT3 通过其转录因子 - 肝脏 X 受体过度表达的潜力 (LXR) 激活可改善急性脂毒性中心肌细胞的结构和功能。