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

这项建议将研究硒(Se)循环酶--硒半胱氨酸裂解酶的作用 (SCLY)，再加上高果糖和饮食中的硒缺乏会影响心脏功能。硒 缺乏症与心脏代谢紊乱的风险增加有关，包括2型 糖尿病(T2D)和动脉粥样硬化。人类心脏代谢紊乱(如T2D)的一个驱动因素是 过量摄入果糖。高果糖饮食已被证明会导致胰岛素抵抗，氧化 应激和心脏脂质物种，如三酰甘油和二酰甘油，与 心血管疾病(CVD)，在大多数组织中，硒通过控制氧化还原平衡来维持氧化还原动态平衡 硒蛋白水平，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)，抑制活性氧物种(ROS)，在这种情况下 Gpx4，调节铁性下垂。然而，目前尚不清楚Scly是否调节体内的硒和硒蛋白水平 心脏，尤其是在接触高果糖饮食的情况下。在依赖硒的组织中，如肝脏， 特别是当硒是有限的时，硒蛋白的降解可能成为硒蛋白的硒来源， 即硒的循环，这是一种由硒半胱氨酸裂解酶(Scly)进行的反应。在中国的实验 这一建议将决定心脏如何代谢和循环硒，从而影响硒蛋白水平。 在低硒状态和高果糖饮食相结合的情况下，运动和整体心脏功能。目标1 将决定高果糖饮食是否会激活心脏中的硒循环。目标2将 确定Scly是否能降低缺硒心肌细胞的氧化应激和铁性下垂。这个 这一建议的总体影响是理解心脏中的硒代谢和循环是如何调节的 在高果糖环境中，局部硒水平和调节心脏生理。这将为我们提供指导 补充硒或辅助使用纳米颗粒的营养建议的改进 治疗心血管疾病的治疗方法。

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.