Mechanism of metabolic remodeling in the diabetic heart

项目摘要 为了补偿减少的葡萄糖氧化，糖尿病心肌细胞增加脂质摄取。由于 线粒体功能障碍，心肌细胞不能有效地利用脂质，导致脂肪乙酰积累 辅酶A是脂肪酸氧化的产物。高水平的乙酰辅酶A通过诱导产酮速率来促进生酮。 限制酶3-羟基-3-甲基戊二酰-CoA-合酶-2（HMGCS 2），其产生酮体。 生酮通过酮解抑制酮体消耗，其中限速酶是琥珀酰辅酶A： 3-含氧酸CoA转移酶（SCOT）。减少酮分解减少糖尿病心脏的能量。在我们的小说里 在心肌细胞中具有心脏特异性过表达的糖尿病秋田小鼠（秋田/miR-133 aTg）、心肌细胞内 防止脂质积聚。我们的研究显示miR-133 a靶向锌指E-box的3/UTR， 成键同源框（ZEB）。ZEB抑制线粒体脱乙酰酶sirtuin-3（SIRT 3）。SIRT 3改善 线粒体功能通过脱乙酰化激活线粒体蛋白来实现。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：糖尿病心肌中miR-133 a的过表达会促进脂肪酸代谢，从而降低血脂 积累和酮生成，其总体上刺激酮分解，导致能量效率提高。 目的1：检验增加的心脏miR-133 a改善脂肪酸代谢以减少心肌缺血的假设。 通过靶向ZEB来减少糖尿病心脏中的脂质积聚。评估miR-133 a对糖尿病的影响- 诱导糖尿病心脏中FA摄取和代谢、ZEB和脂质积聚。 目的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的假设 糖尿病心脏通过上调HMGCS 2。评价SIRT 3对脂肪乙酰辅酶A、HMGCS 2和HMGCS 3的影响。 糖尿病心脏的生酮作用 目的3：检验心脏生酮阻止酮分解以减少糖尿病患者能量的假设 心脏抑制SCOT。评价HMGCS 2抑制的糖尿病心脏中的酮分解和心脏能量。 影响：这些目标的完成将：1）提高我们对DM代谢重塑的认识 2）提供新的分子靶点来调节DM心脏中的代谢通量，3）提供对 改善糖尿病心脏的心脏能量效率，以及4）提供可以在 代谢紊乱的非糖尿病性心力衰竭。

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.