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.

这项建议将探讨硒（Se）-回收酶，硒半胱氨酸裂解酶的作用 （Scly），结合高果糖和膳食硒缺乏影响心脏功能。Se 缺乏与心血管代谢紊乱的风险增加有关，包括2型 糖尿病（T2 D）和动脉粥样硬化。心脏代谢紊乱如人类T2 D的驱动因素是 果糖摄入过多。高果糖饮食已被证明会诱导胰岛素抵抗，氧化 应激和心脏脂质物质如三酰基甘油和二酰基甘油， 在大多数组织中，硒通过控制细胞内的氧化还原平衡来维持氧化还原平衡。 硒蛋白水平，如谷胱甘肽过氧化物酶1和4（GPX 1和GPX 4）和硫氧还蛋白 还原酶1和2（TXNRD 1和TXNRD 2），其抑制活性氧（ROS），并且在这种情况下， GPX 4调节铁凋亡。然而，尚不清楚Scly是否能调节小鼠体内硒和硒蛋白的水平。 心脏，特别是在高果糖饮食中。在硒依赖性组织如肝脏中， 特别是当硒含量有限时，硒蛋白降解可能成为硒蛋白的硒源， 即硒再循环，通过酶硒代半胱氨酸裂解酶（Scly）进行的反应。中的实验 这一提议将确定心脏如何代谢和吸收硒，从而影响硒蛋白水平 和活动，以及整体心脏功能在缺硒状态结合高果糖饮食。要求1 将决定是否硒循环在心脏中被激活，以响应高果糖饮食。目标2将 确定Scly的作用是否能降低缺硒心肌细胞的氧化应激和铁凋亡。的 这一建议的总体影响是了解硒代谢和心脏中的再循环如何调节 局部硒水平和调节心脏生理在高果糖环境。这将指导 通过补充硒或辅助使用纳米颗粒改善营养建议 治疗CVD的药物。