A Critical Role for PPARα-Mediated Lipotoxicity in the Pathogenesis of Diabetic Cardiomyopathy: Modulation by Dietary Fat Content

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 100; no. 3; pp. 1226 - 1231
• Main Authors: Finck, Brian N., Han, Xianlin, Courtois, Michael, Aimond, Franck, Nerbonne, Jeanne M., Kovacs, Attila, Gross, Richard W., Kelly, Daniel P.
• Format: Journal Article
• Language: English
• Published: National Academy of Sciences 04.02.2003; National Acad Sciences; The National Academy of Sciences
• Subjects: Biological Sciences; Cardiomyopathies; Diabetes; Diabetes complications; Diabetic cardiomyopathies; Fatty acids; Heart; Lipids; Mice; Type 2 diabetes mellitus; Vehicles
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0336724100

To explore the role of peroxisome proliferator-activated receptor $\alpha\>(PPAR\alpha)$-mediated derangements in myocardial metabolism in the pathogenesis of diabetic cardiomyopathy, insulinopenic mice with PPARα deficiency (PPARα-/-) or cardiac-restricted overexpression [myosin heavy chain (MHC)-PPAR] were characterized. Whereas PPARα-/-mice were protected from the development of diabetes-induced cardiac hypertrophy, the combination of diabetes and the MHC-PPAR genotype resulted in a more severe cardiomyopathic phenotype than either did alone. Cardiomyopathy in diabetic MHC-PPAR mice was accompanied by myocardial long-chain triglyceride accumulation. The cardiomyopathic phenotype was exacerbated in MHC-PPAR mice fed a diet enriched in triglyceride containing long-chain fatty acid, an effect that was reversed by discontinuing the high-fat diet and absent in mice given a medium-chain triglyceride-enriched diet. Reactive oxygen intermediates were identified as candidate mediators of cardiomyopathic effects in MHC-PPAR mice. These results link dysregulation of the PPARα gene regulatory pathway to cardiac dysfunction in the diabetic and provide a rationale for serum lipid-lowering strategies in the treatment of diabetic cardiomyopathy.