Abstract 14197: Cardiac Steatosis Induced by Cardiomyocyte-specific Adipose Triglyceride Lipase Deficiency is Associated with Impaired Oxidative Substrate Metabolism and Hypertrophy
Despite the association between myocardial steatosis and cardiac dysfunction it remains unclear whether increased cardiac lipid accumulation in the absence of increased fatty acid uptake or genetically defective fatty acid oxidation contributes to the development of cardiac dysfunction. Since adipose triglyceride lipase (ATGL) is rate-limiting for triacylglycerol (TG) catabolism and thus regulates myocardial lipid accumulation, we utilized a mouse model with tamoxifen-inducible cardiomyocyte-specific ATGL deficiency (ATGL-KO) to test whether impaired cardiomyocyte TG lipolysis and ensuing cardiac steatosis influences cardiac function and metabolism. Five weeks following tamoxifen treatment, ATGL-KO mice exhibited marked cardiac steatosis as was evident from 9-fold increased myocardial TG content (ATGL-KO: 373.2±29.7, control: 43.3±5 nmol TG/mg protein, mean±SEM, n=5, p<1x10-5) and whitish discoloration of ATGL-KO hearts. Interestingly, ATGL-KO hearts also exhibited increased diacylglycerol content while long chain acyl-CoA species and ceramides were decreased or unchanged. Examination of in vivo heart function using echocardiography showed decreased ejection fraction in hearts from ATGL-KO mice (ATGL-KO: 48.0±2.6, control: 60.0±2.8%, mean±SEM, n=5-9, p=0.01). Furthermore, ATGL-KO hearts displayed hypertrophic remodeling, as was evident from increased heart weight to tibia length ratio, ventricular wall dimensions, and expression of the hypertrophy marker genes brain natriuretic peptide and beta myosin heavy chain. Histological analysis using Masson's trichrome stained heart sections also revealed extensive fibrosis in ATGL-KO hearts. To determine the effect of ATGL deficiency on oxidative substrate metabolism, hearts were perfused ex vivo in the working mode. In ATGL-KO hearts, oleate and glucose oxidation rates were decreased by 80 and 55% (n=5-6, p<0.01), respectively, which was accompanied by a 49% reduction in ATP to AMP ratio (n=5-6, p<0.05). Collectively, these findings suggest that diminished myocardial TG catabolism and ensuing steatosis impairs oxidative metabolism and leads to hypertrophic remodeling and systolic dysfunction in vivo.
- © 2011 by American Heart Association, Inc.