Abstract 18054: Metabolic Remodeling in Mice with Cardiomyocyte-Specific Fatty Acid Overload
Introduction: In obesity it is unclear how lipid accumulation in the cardiomyocyte contributes to the pathophysiology of metabolic heart disease (MHD). Potential mechanisms of lipid-induced dysfunction include toxic effects or signaling from lipid species and/or increased mitochondrial reactive oxygen species (ROS) production to decrease mitochondrial function. To determine how excess cardiomyocyte lipids mediate MHD, we measured lipid metabolites, lipid sensitive signaling and ROS production in mice with cardiomyocyte-specific overexpression of the fatty acid transport protein-1 (FATP1) in which increased uptake of fatty acids (FA) leads to MHD in the absence of systemic obesity or perturbation of systemic lipid metabolism.
Hypothesis: Accumulation of FA in the cardiomyocyte leads to mitochondrial dysfunction and MHD via lipid metabolites and/or mitochondrial oxidant production.
Methods and Results: FATP1 and wild type (WT) mice were studied at 5-8 weeks of age. In FATP1 hearts, LC-MS showed increased long-chain diacylglycerol (DG) species (+200-300%, p<0.05 vs. WT; DG 18:2-22:6, DG 18:1-22:6, and DG18:0-20:4), without changes in ceramide or acylcarnitine. The activity of the DG target, protein kinase C (phospho PKC beta-II Ser660), was increased by 381±41% (p<0.001 vs. WT) in FATP1 hearts. AKT activity (phospho Ser473), whose downregulation is a measure of PKC-mediated insulin resistance, was decreased by 24±7% in FATP1 hearts (p<0.05 vs. WT). These changes were associated with our previously reported decrease in PGC1α expression and mitochondrial function. H2O2 production (by Amplex Red) from isolated mitochondria was unchanged in FATP1 hearts, and transgenic expression of peroxisomal or mitochondrial catalase in FATP1 hearts had no effect on cardiac hypertrophy (total wall thickness) or diastolic function (Em).
Conclusions: Excessive delivery of FA to the cardiomyocyte leads to long-chain DG accumulation that is associated with PKC activation and downregulation of mitochondrial biogenesis. Toxic lipid intermediates and mitochondrial ROS production do not appear to contribute to MHD in FATP1 mice. These data suggest that cardiomyocyte FA excess, per se, downregulates mitochondrial function through DG-associated signaling.
Author Disclosures: A. Elezaby: None. A.L. Sverdlov: None. V.H. Tu: None. F. Qin: None. J. Rimer: None. J.E. Schaffer: None. W.S. Colucci: None. E.J. Miller: None.
- © 2014 by American Heart Association, Inc.