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

Abstract

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-α (myosin heavy chain [MHC]-PPARα mice) exhibit phenotypic features of the diabetic heart, which are rescued by deletion of CD36, a fatty acid transporter, despite persistent activation of PPARα 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-PPARα mice with mice deficient for cardiac lipoprotein lipase (hsLpLko). MHC-PPARα/hsLpLko mice exhibit improved cardiac function and reduced myocardial triglyceride content compared with MHC-PPARα mice. Surprisingly, in contrast to MHC-PPARα/CD36ko mice, the activity of the cardiac PPARα gene regulatory pathway is normalized in MHC-PPARα/hsLpLko mice, suggesting that PPARα ligand activity exists in the lipoprotein particle. Indeed, LpL mediated hydrolysis of very-low-density lipoprotein activated PPARα 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-PPARα mouse hearts acquire excess lipoprotein-derived lipids. LpL deficiency rescues myocyte triglyceride accumulation, mitochondrial gene regulatory derangements, and contractile function in MHC-PPARα mice. Finally, LpL serves as a source of activating ligand for PPARα in the cardiomyocyte.