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.

项目摘要为了补偿葡萄糖氧化减少，糖尿病心肌细胞会增加脂质摄取。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基的积累 COA，脂肪酸氧化的产物。高水平的乙酰COA通过诱导速率来促进生酮发生限制酶3-羟基-3-甲基戊二酰-COA-synthase-2（HMGCS2），产生酮体。生酮发生通过酮溶解抑制酮体的消耗，其中限速酶是琥珀酰辅酶A： 3-氧酸酸COA转移酶（SCOT）。减少的酮解会降低糖尿病心脏的能量。在我们的小说中心肌细胞（Akita/mir-133ATG），心脏内细胞中的心脏特异性过表达的糖尿病秋田小鼠防止脂质积累。我们的调查显示，miR-133a靶向3/锌指E-box-的UTR 粘合同源物（ZEB）。 ZEB抑制线粒体脱乙酰基酶Sirtuin-3（SIRT3）。 SIRT3改善线粒体功能通过脱乙酰化激活线粒体蛋白。线粒体功能增加减少脂肪乙酰COA积累，这是生酮发生和脂质积累所必需的。假设：DM心脏中miR-133a的过表达将促进脂肪酸代谢以降低脂质积累和生酮发生，总体刺激酮解体，从而提高了能源效率。 AIM 1：测试心脏miR-133a增加的假设可改善脂肪酸代谢以减少通过靶向ZEB，脂质的积累在糖尿病心脏中。评估miR-133a对糖尿病的影响 - 糖尿病心脏中诱导的FA摄取和代谢，ZEB和脂质积累。 AIM 2：检验以下假设，即增加线粒体中脂肪乙酰基CoA会诱导生酮发生在糖尿病心脏通过上调HMGCS2。评估SIRT3对脂肪乙酰COA，HMGCS2和糖尿病心脏中的生酮发生。目标3：测试心脏生酮发生可防止酮解的假设，以减少糖尿病的能量通过抑制苏格兰人的心。评估HMGCS2抑制糖尿病心脏中的酮溶解和心脏能量。影响：这些目标的完成将：1）增强我们对DM中代谢重塑的知识心脏，2）提供新的分子靶标，以调节DM心脏中的代谢通量，3）提供见识提高糖尿病心脏的心脏能源效率，4）可以在非糖尿病性心力衰竭，代谢被扰乱。