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
Open Access
- 26 January 2010
- journal article
- research article
- Published by Ovid Technologies (Wolters Kluwer Health) in Circulation
- Vol. 121 (3), 426-435
- https://doi.org/10.1161/CIRCULATIONAHA.109.888735
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.This publication has 55 references indexed in Scilit:
- The Pathologic Continuum of Diabetic Vascular DiseaseJournal of the American College of Cardiology, 2009
- Triglyceride-rich lipoprotein lipolysis releases neutral and oxidized FFAs that induce endothelial cell inflammationJournal of Lipid Research, 2009
- Transcriptional coactivators PGC-1α and PGC-lβ control overlapping programs required for perinatal maturation of the heartGenes & Development, 2008
- Nuclear receptors PPARβ/δ and PPARα direct distinct metabolic regulatory programs in the mouse heartJCI Insight, 2007
- Cardiomyocyte expression of PPARγ leads to cardiac dysfunction in miceJCI Insight, 2007
- CD36 Deficiency Rescues Lipotoxic CardiomyopathyCirculation Research, 2007
- PGC-1α Deficiency Causes Multi-System Energy Metabolic Derangements: Muscle Dysfunction, Abnormal Weight Control and Hepatic SteatosisPLoS Biology, 2005
- Lipoprotein Lipase-mediated Selective Uptake from Low Density Lipoprotein Requires Cell Surface Proteoglycans and Is Independent of Scavenger Receptor Class B Type 1Published by Elsevier BV ,2000
- RGS4 causes increased mortality and reduced cardiac hypertrophy in response to pressure overloadJCI Insight, 1999
- Macrophage lipoprotein lipase promotes foam cell formation and atherosclerosis in vivoJCI Insight, 1999