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A critical role for PPARa-mediated lipotoxicity in the pathogenesis of diabetic cardiomyopathy: Modulation by dietary fat content



A critical role for PPARa-mediated lipotoxicity in the pathogenesis of diabetic cardiomyopathy: Modulation by dietary fat content



Proceedings of the National Academy of Sciences of the United States of America 100(3): 26-31



The role of peroxisome proliferator-activated receptor a (PPARa)-mediated derangements in myocardial metabolism in the pathogenesis of diabetic cardiomyopathy was investigated. Insulinopenic mice with PPARa deficiency (PPARa-/-) or cardiac-restricted overexpression (myosin heavy chain (MHC)-PPAR) were characterized. The PPARa-/- mice were protected from the development of diabetes-induced cardiac hypertrophy, but the combination of diabetes and the MHC-PPAR genotype resulted in a more severe cardiomyopathic phenotype, which was exacerbated by a diet enriched in triglyceride containing long-chain fatty acid. This effect was reversed by discontinuing the high-fat diet and was absent in mice fed a medium-chain triglyceride-enriched diet. The results show the link between dysregulation of the PPARa gene regulatory pathway and cardiac dysfunction in diabetes and provide a rationale for serum lipid-lowering strategies for treating diabetic cardiomyopathy.

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