Mechanism of metabolic remodeling in the diabetic heart

糖尿病心脏代谢重塑机制

基本信息

批准号：
10705337
负责人：
Paras Kumar Mishra
金额：
$ 40.04万
依托单位：
UNIVERSITY OF NEBRASKA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-22 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10705337
关键词：
3-hydroxy-3-methylglutaryl-coenzyme A Acetyl Coenzyme A Acetylation Attenuated Binding Biopsy Cardiac Cardiac Myocytes Carnitine Carrier Proteins Citrate (si)-Synthase Citric Acid Cycle Coenzyme A Coenzyme A-Transferases Consumption Crossbreeding Deacetylase Deacetylation Diabetes Mellitus Enzymes Fatty Acids Genetic Transcription Glucose Heart Heart Transplantation Heart failure Homeobox Hyperglycemia Investigation Ketone Bodies Knowledge Lipids Measures Metabolic Metabolism Mitochondria Mitochondrial Proteins Molecular Molecular Target Mus Myocardial dysfunction Pathogenesis Patients Promoter Regions Proteins Regulation Risk Role Sirtuins Syndrome Testing Transferase Transgenic Mice Untranslated Regions Zinc Fingers beta-adrenergic receptor cardiometabolism diabetic diabetic rat fatty acid metabolism fatty acid oxidation follow-up improved insight ketogenesis mitochondrial dysfunction new therapeutic target non-diabetic novel overexpression oxidation prevent receptor function response succinyl-coenzyme A uptake

项目摘要

PROJECT SUMMARY To compensate for the decreased glucose oxidation, diabetic cardiomyocytes increase lipid uptake. Due to mitochondrial dysfunction, cardiomyocytes could not efficiently utilize lipids leading to accumulation of fatty acetyl CoA, a product of fatty acid oxidation. High levels of acetyl CoA promotes ketogenesis by inducing the rate- limiting enzyme 3-Hydroxy-3-MethylGlutaryl-CoA-Synthase-2 (HMGCS2), which produces ketone bodies. Ketogenesis inhibits consumption of ketone bodies via ketolysis where the rate-limiting enzyme is succinyl-CoA: 3-oxoacid CoA transferase (SCOT). Reduced ketolysis decreases energy in the diabetic heart. In our novel diabetic Akita mice with cardiac-specific overexpression in the cardiomyocytes (Akita/miR-133aTg), intramyocyte lipid accumulation is prevented. Our investigation revealed that miR-133a targets 3/UTR of Zinc finger E-box- bonding homeobox (ZEB). ZEB inhibits mitochondrial deacetylase sirtuin-3 (SIRT3). SIRT3 improves mitochondrial function by activating mitochondrial proteins via deacetylation. Increased mitochondrial function decreases the fatty acetyl CoA accumulation, which is required for both ketogenesis and lipid accumulation. Hypothesis: Overexpression of miR-133a in the DM heart will promote fatty acid metabolism to decrease lipid accumulation and ketogenesis, which overall stimulates ketolysis resulting in improved energy efficiency. Aim 1: Test the hypothesis that increased cardiac miR-133a improves fatty acid metabolism to reduce lipid accumulation in the diabetic heart by targeting ZEB. Evaluate the effect of miR-133a on diabetes- induced FA uptake and metabolism, ZEB, and lipid accumulation in the diabetic heart. Aim 2: Test the hypothesis that increased fatty acetyl CoA in mitochondria induces ketogenesis in the diabetic heart by upregulating HMGCS2. Evaluate the effect of SIRT3 on fatty acetyl CoA, HMGCS2, and ketogenesis in the diabetic heart. Aim 3: Test the hypothesis that cardiac ketogenesis prevents ketolysis to reduce energy in the diabetic heart by suppressing SCOT. Evaluate ketolysis and cardiac energy in the HMGCS2-inhibited diabetic heart. Impact: The completion of these aims will: 1) enhance our knowledge on metabolic remodeling in the DM heart, 2) provide new molecular targets to modulate metabolic flux in the DM heart, 3) provide insight to improve cardiac energy efficiency in the diabetic heart, and 4) render metabolic targets that can be tested in non-diabetic heart failure where metabolism is deranged.

项目概要为了补偿葡萄糖氧化的减少，糖尿病心肌细胞增加脂质摄取。由于线粒体功能障碍，心肌细胞无法有效利用脂质，导致脂肪乙酰积累 CoA，脂肪酸氧化的产物。高水平的乙酰辅酶A通过诱导速率来促进生酮限制酶 3-Hydroxy-3-MmethylGlutaryl-CoA-Synthase-2 (HMGCS2)，可产生酮体。生酮通过酮解抑制酮体的消耗，其中限速酶是琥珀酰辅酶A： 3-含氧酸 CoA 转移酶 (SCOT)。酮解减少会降低糖尿病心脏的能量。在我们的小说里糖尿病秋田小鼠心肌细胞中心脏特异性过度表达 (Akita/miR-133aTg)、肌细胞内防止脂质积累。我们的研究表明 miR-133a 靶向锌指 E-box 的 3/UTR- 键合同源盒（ZEB）。 ZEB 抑制线粒体脱乙酰酶 Sirtuin-3 (SIRT3)。 SIRT3 改进通过脱乙酰化激活线粒体蛋白来发挥线粒体功能。线粒体功能增强减少脂肪乙酰辅酶A的积累，这是生酮和脂质积累所必需的。假设：糖尿病心脏中miR-133a的过度表达会促进脂肪酸代谢从而降低血脂积累和生酮，总体上刺激酮解作用，从而提高能量效率。目标 1：检验心脏 miR-133a 增加可改善脂肪酸代谢以减少脂肪酸代谢的假设通过靶向 ZEB 治疗糖尿病心脏中的脂质积累。评估 miR-133a 对糖尿病的影响诱导糖尿病心脏中的 FA 摄取和代谢、ZEB 和脂质积累。目标 2：检验线粒体中脂肪乙酰辅酶 A 增加会诱导线粒体中生酮作用的假设通过上调 HMGCS2 来治疗糖尿病心脏病。评估 SIRT3 对脂肪乙酰 CoA、HMGCS2 和糖尿病心脏的生酮作用。目标 3：检验心脏生酮阻止酮解作用以减少糖尿病患者能量的假设通过抑制 SCOT 来心脏。评估 HMGCS2 抑制的糖尿病心脏的酮解作用和心脏能量。影响：这些目标的完成将：1）增强我们对糖尿病代谢重塑的了解心脏，2) 提供新的分子靶标来调节 DM 心脏的代谢通量，3) 提供洞察提高糖尿病心脏的能量效率，4) 提供可在以下方面进行测试的代谢目标新陈代谢紊乱的非糖尿病性心力衰竭。