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

Brian N. Finck, Xianlin Han, Michael Courtois, Franck Aimond, Jeanne M. Nerbonne, Attila Kovacs, Richard W. Gross, Daniel P. Kelly

Research output: Contribution to journalArticle

409 Scopus citations

Abstract

To explore the role of peroxisome proliferator-activated receptor α (PPARα)-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 longchain 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.

Original languageEnglish (US)
Pages (from-to)1226-1231
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume100
Issue number3
DOIs
StatePublished - Feb 4 2003
Externally publishedYes

ASJC Scopus subject areas

  • General

Fingerprint Dive into the research topics of 'A critical role for PPARα-mediated lipotoxicity in the pathogenesis of diabetic cardiomyopathy: Modulation by dietary fat content'. Together they form a unique fingerprint.

  • Cite this