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Principal Investigator: Briana Shimada
Organization: UNIVERSITY OF HAWAII AT MANOA
Fiscal Year: 2024
Award: $155,398
Funding agency: National Institute of General Medical Sciences
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.
Terms: <1,2-diacylglycerol><Active Oxygen><Adult-Onset Diabetes Mellitus><Atherosclerosis><Atherosclerotic Cardiovascular Disease><Autoregulation><Body Tissues><Cardiac><Cardiac Muscle Cells><Cardiac Myocytes><Cardiocyte><Cardiometabolic Disease><Cardiometabolic Disorder><Cardiovascular Diseases><Consumption><Diacylglycerols><Diet><Dietary Selenium><Diglycerides><Environment><Enzyme Gene><Enzymes><Exposure to><Fructose><Health><Heart><Heart Muscle Cells><Heart myocyte><Homeostasis><Human><Insulin Resistance><Intermediary Metabolism><Ketosis-Resistant Diabetes Mellitus><Levulose><Lipids><Liver><Maturity-Onset Diabetes Mellitus><Metabolic Processes><Metabolism><Modern Man><NIDDM><Non-Insulin Dependent Diabetes><Non-Insulin-Dependent Diabetes Mellitus><Noninsulin Dependent Diabetes><Noninsulin Dependent Diabetes Mellitus><Nutritional><Oxidation-Reduction><Oxidative Stress><Oxygen Radicals><Physiological Homeostasis><Physiology><Pro-Oxidants><Reaction><Reactive Oxygen Species><Recommendation><Recycling><Redox><Role><Se element><Selenium><Slow-Onset Diabetes Mellitus><Source><Stable Diabetes Mellitus><Supplementation><T2 DM><T2D><T2DM><Tissues><Triacylglycerol><Triglycerides><TrxR1 enzyme><Type 2 Diabetes Mellitus><Type 2 diabetes><Type II Diabetes Mellitus><Type II diabetes><adult onset diabetes><atheromatosis><atherosclerotic disease><atherosclerotic vascular disease><cardiac function><cardiometabolic risk><cardiomyocyte><cardiovascular disorder><diacylglycerol><dietary><diets><diglyceride><experiment><experimental research><experimental study><experiments><function of the heart><glutathione peroxidase><heart function><hepatic body system><hepatic organ system><improved><insulin resistant><insulin tolerance><ketosis resistant diabetes><maturity onset diabetes><nanoparticle therapy><nutritious><oxidation reduction reaction><precision nutrition><response><selenium deficiency><selenocysteine beta-lyase><selenocysteine lyase><selenoprotein><social role><therapeutic nanoparticles><thioredoxin reductase 1><type 2 DM><type II DM><type two diabetes>