Abstract 15711: Diabetes-Induced Cardiac Dysfunction is Attenuated in Mice with Cardiomyocyte-specific Adipose Triglyceride Lipase Over-expression
Diabetic cardiomyopathy is associated with enhanced myocardial triacylglycerol (TAG) deposition suggesting that the enzymes controlling TAG levels in the heart may be altered during diabetes. Since cardiomyocyte TAG catabolism is mediated by the TAG hydrolase, adipose triglyceride lipase (ATGL), we assessed whether diabetes influences cardiac ATGL to modulate TAG levels and subsequently contribute to the pathogenesis of diabetic cardiomyopathy. ATGL protein expression and cardiac TAG levels were measured in genetic and pharmacological models of type 1 diabetes. Cardiac ATGL protein expression was increased in both Akita and streptozotocin (STZ, 185 mg/kg, i.p.) induced type 1 diabetic mice, which was paralleled by an increase in cardiac TAG content in both models. To determine whether this change in cardiac ATGL during diabetes is detrimental or beneficial for cardiac function, a mouse model with cardiac-specific overexpression of ATGL (MHC-ATGL) was utilized and studied four-weeks post saline or STZ treatment. While STZ-induced hyperglycemia, hyperlipidemia and body weight loss were comparable between genotypes, echocardiographic and histological analysis revealed significantly less pronounced cardiac dilatation and systolic dysfunction in the diabetic MHC-ATGL mice when compared to the WT (%EF; WT-STZ vs. MHC-ATGL-STZ; 50.4±1.65 vs. 62.6±1.393, mean±SEM, n=7-8, p<0.001). Furthermore, diabetes also augmented myocardial TAG levels in WT but not MHC-ATGL hearts (WT-STZ vs. MHC-ATGL-STZ; 53.01±7.6 vs. 15.6±2.9 nmol TAG per mg protein, mean±SEM, n=7-8, p<0.001). Consistent with the alterations in lipid accumulation following diabetes, WT but not MHC-ATGL hearts exhibited increased protein expression of PPAR alpha and its downstream target genes, perilipin-5 (lipid droplet binding protein), CD36 (fatty acid transporter), and UCP3 (uncoupling protein), which are involved in fatty acid metabolism. Collectively, these findings suggest that 1) increased cardiac ATGL during diabetes is an adaptive, albeit insufficient response to compensate for the increased accumulation of myocardial TAG and 2) overexpression of ATGL prevents diabetes induced steatosis and cardiomyopathy.
- © 2011 by American Heart Association, Inc.