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.

该提议将研究硒（SE） - 恢复酶，硒代半胱氨酸裂解酶的作用 （SCLY），结合高果糖和饮食中的SE缺乏会影响心脏功能。 se 缺乏症与心脏代谢疾病（包括2型）的风险增加有关 糖尿病（T2D）和动脉粥样硬化。人类中T2D等心脏代谢性疾病的驱动程序是 果糖过度消费。高饮食果糖已显示出诱导胰岛素抵抗，氧化性 胁迫和心脏脂质物种，例如三酰基甘油和与之相关的二酰基甘油 在大多数组织中，心血管疾病（CVD）通过控制来维持氧化还原稳态 硒蛋白的水平，例如谷胱甘肽过氧化物酶1和4（GPX1和GPX4）和硫氧还蛋白 还原酶1和2（TXNRD1和TXNRD2），遏制活性氧（ROS），在此情况下 GPX4调节铁铁作用。但是，尚不清楚SCLY是否在SE中调节SE和硒蛋白水平 心脏，特别是在暴露于高果糖饮食时。在SE依赖性组织中，例如肝脏， 特别是在局限性的情况下，硒蛋白降解可能成为硒蛋白的SE来源， 即Se回收，这是由酶硒代蛋白裂解酶（SCLY）进行的反应。实验 该建议将决定心脏如何代谢和回收SE，从而影响硒蛋白水平 和活动，以及在疾病状态下的总体心脏功能以及高果糖饮食的结合。目标1 将确定在高果糖饮食中，心脏中是否会激活SE回收。 AIM 2意志 确定SCLY作用是否减少了缺乏的心肌细胞中的氧化应激和铁毒性。这 该提议的总体影响是了解SE代谢和回收如何调节 局部SE水平并调节高果糖环境中的心脏生理学。这将指导 补充SE的营养建议改进或有助于使用纳米颗粒 治疗CVD的治疗剂。