Mechanism of metabolic remodeling in the diabetic heart

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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.