Rescue of Cardiomyopathy in Peroxisome Proliferator-Activated Receptor-α Transgenic Mice by Deletion of Lipoprotein Lipase Identifies Sources of Cardiac Lipids and Peroxisome Proliferator-Activated Receptor-α Activators

Background-Emerging evidence in obesity and diabetes mellitus demonstrates that excessive myocardial fatty acid uptake and oxidation contribute to cardiac dysfunction. Transgenic mice with cardiac-specific overexpression of the fatty acid-activated nuclear receptor peroxisome proliferator-activated receptor-alpha (myosin heavy chain [MHC]-PPAR alpha mice) exhibit phenotypic features of the diabetic heart, which are rescued by deletion of CD36, a fatty acid transporter, despite persistent activation of PPAR alpha gene targets involved in fatty acid oxidation. Methods and Results-To further define the source of fatty acid that leads to cardiomyopathy associated with lipid excess, we crossed MHC-PPAR alpha mice with mice deficient for cardiac lipoprotein lipase (hsLpLko). MHC-PPAR alpha/hsLpLko mice exhibit improved cardiac function and reduced myocardial triglyceride content compared with MHC-PPAR alpha mice. Surprisingly, in contrast to MHC-PPAR alpha/CD36ko mice, the activity of the cardiac PPAR alpha gene regulatory pathway is normalized in MHC-PPAR alpha/hsLpLko mice, suggesting that PPAR alpha ligand activity exists in the lipoprotein particle. Indeed, LpL mediated hydrolysis of very-low-density lipoprotein activated PPAR alpha in cardiac myocytes in culture. The rescue of cardiac function in both models was associated with improved mitochondrial ultrastructure and reactivation of transcriptional regulators of mitochondrial function. Conclusions-MHC-PPAR alpha mouse hearts acquire excess lipoprotein-derived lipids. LpL deficiency rescues myocyte triglyceride accumulation, mitochondrial gene regulatory derangements, and contractile function in MHC-PPAR alpha mice. Finally, LpL serves as a source of activating ligand for PPAR alpha in the cardiomyocyte. (Circulation. 2010;121:426-435.)