Mechanism of metabolic remodeling in the diabetic heart

项目总结 为了补偿减少的葡萄糖氧化，糖尿病心肌细胞增加了脂质摄取。由于 线粒体功能障碍，心肌细胞不能有效利用脂类导致脂肪乙酰积聚 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 限制酶3-羟基-3-甲基戊二酰辅酶A合成酶-2(HMGCS2)，产生酮体。 酮生成通过酮解来抑制酮体的消耗，其中限速酶是琥珀酰辅酶A： 3-氧酸辅酶A转移酶(SCOT)。减少酮体分解会降低糖尿病患者心脏的能量。在我们的小说中 糖尿病秋田鼠心肌细胞(Akita/miR-133aTg)、心肌细胞内心脏特异性高表达 防止脂肪堆积。我们的研究表明，miR-133a针对的是锌指E盒的3/UtR。 结合同源盒(ZEB)。ZeB抑制线粒体脱乙酰酶sirtuin-3(SIRT3)。改进了SIRT3 线粒体通过脱乙酰基激活线粒体蛋白来发挥功能。线粒体功能增强 减少脂肪乙酰辅酶A的积累，这是酮合成和脂肪积累所必需的。 假说：糖尿病心脏miR-133a过表达可促进脂肪酸代谢降脂 积累和酮类生成，总体上刺激酮类分解，从而提高能量效率。 目的1：验证心脏miR-133a增加改善脂肪酸代谢降低的假说 通过靶向Zeb在糖尿病心脏中积累脂质。评价miR-133a对糖尿病的作用 诱导糖尿病大鼠心脏对FA的摄取和代谢、ZEB和脂质堆积。 目的2：验证线粒体脂肪乙酰辅酶A增加诱导酮的生成的假说。 上调HMGCS2对糖尿病心脏的作用。评价SIRT3对脂肪乙酰辅酶A、HMGCS2和 糖尿病心脏中的酮体生成。 目的3：在糖尿病患者中验证酮生成阻止酮体溶解以减少能量的假设 通过压制苏格兰人来打动人心。评价HMGCS2抑制的糖尿病心脏的酮体分解和心脏能量。 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)提供新的分子靶点来调节糖尿病心脏的代谢流量，3)提供洞察力 改善糖尿病心脏的心脏能量效率，以及4)提供可在 代谢紊乱的非糖尿病心力衰竭。

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.