Selenium Metabolism in the Heart: Impact of High Fructose and Low Selenium

心脏中的硒代谢：高果糖和低硒的影响

• 批准号: 10793881
• 负责人: Briana Shimada
• 金额: $ 16.8万
• 依托单位: UNIVERSITY OF HAWAII AT MANOA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-01 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10793881
• 关键词: Atherosclerosis; Cardiac; Cardiac Myocytes; Cardiometabolic Disease; Cardiovascular Diseases; Consumption; Diet; Dietary Selenium; Diglycerides; Environment; Enzymes; Exposure to; Fructose; Health; Heart; Homeostasis; Human; Insulin Resistance; Lipids; Liver; Metabolism; Non-Insulin-Dependent Diabetes Mellitus; Nutritional; Oxidation-Reduction; Oxidative Stress; Physiology; Reaction; Reactive Oxygen Species; Recommendation; Recycling; Role; Selenium; Source; Supplementation; Tissues; Triglycerides; cardiometabolic risk; dietary; experimental study; glutathione peroxidase; heart function; improved; precision nutrition; response; selenium deficiency; selenocysteine lyase; selenoprotein; therapeutic nanoparticles; thioredoxin reductase 1

This proposal will investigate the role of the selenium (Se)-recycling enzyme, selenocysteine lyase (Scly), in combination with high fructose and dietary Se deficiency impacts cardiac function. Se deficiency has been associated with an increased risk of cardiometabolic disorders including type 2 diabetes (T2D) and atherosclerosis. A driver of cardiometabolic disorders such as T2D in humans is the overconsumption of fructose. High dietary fructose has been shown to induce insulin resistance, oxidative stress and cardiac lipid species such as triacylglycerols and diacylglycerols that are associated with cardiovascular diseases (CVDs), In most tissues, Se maintains redox homeostasis by controlling the levels of selenoproteins, such as glutathione peroxidases 1 and 4 (GPX1 and GPX4) and thioredoxin reductases 1 and 2 (TXNRD1 and TXNRD2), that curb reactive oxygen species (ROS), and in the case of GPX4, regulates ferroptosis. However, it is unknown if Scly modulates Se and selenoprotein levels in the heart, especially upon exposure to a high- fructose diet. In Se-dependent tissues such as the liver, especiallywhen Se is limiting, selenoprotein degradation may become a source of Se for selenoproteins, i.e. Se recycling, a reaction carried out by the enzyme selenocysteine lyase (Scly). The experiments in this proposal will determine how the heart metabolizes and recycles Se, impacting selenoprotein levels and activity, and overall heart function in Se- deficient states combined with a high fructose diet. Aim 1 will determine if Se recycling is activated in the heart in response to a high fructose diet. Aim 2 will determine if Scly action reduces oxidative stress and ferroptosis in Se-deficient cardiomyocytes. The overall impact of this proposal is to understand how Se metabolism and recycling in the heart regulates local Se levels and modulates heart physiology in a high fructose environment. This will guide improvements on nutritional recommendations with Se supplementation or aid in the use of nanoparticle therapeutics to treat CVD.

本课题将探讨硒（Se）回收酶——硒半胱氨酸裂解酶的作用