CD36 deficiency rescues lipotoxic cardiomyopathy

John Yang, Nandakumar Sambandam, Xianlin Han, Richard W. Gross, Michael Courtois, Attila Kovacs, Maria Febbraio, Brian N. Finck, Daniel P. Kelly

Research output: Contribution to journalArticlepeer-review

169 Scopus citations

Abstract

Obesity-related diabetes mellitus leads to increased myocardial uptake of fatty acids (FAs), resulting in a form of cardiac dysfunction referred to as lipotoxic cardiomyopathy. We have shown previously that chronic activation of the FA-activated nuclear receptor, peroxisome proliferator-activated receptor α (PPARα), is sufficient to drive the metabolic and functional abnormalities of the diabetic heart. Mice with cardiac-restricted overexpression of PPARα (myosin heavy chain [MHC]-PPARα) exhibit myocyte lipid accumulation and cardiac dysfunction. We sought to define the role of the long-chain FA transporter CD36 in the pathophysiology of lipotoxic forms of cardiomyopathy. MHC-PPARα mice were crossed with CD36-deficient mice (MHC-PPARα/CD36 mice). The absence of CD36 prevented myocyte triacylglyceride accumulation and cardiac dysfunction in the MHC-PPARα mice under basal conditions and following administration of high-fat diet. Surprisingly, the rescue of the MHC-PPARα phenotype by CD36 deficiency was associated with increased glucose uptake and oxidation rather than changes in FA utilization. As predicted by the metabolic changes, the activation of PPARα target genes involved in myocardial FA-oxidation pathways in the hearts of the MHC-PPARα mice was unchanged in the CD36-deficient background. However, PPARα-mediated suppression of genes involved in glucose uptake and oxidation was reversed in the MHC-PPARα/ CD36 mice. We conclude that CD36 is necessary for the development of lipotoxic cardiomyopathy in MHC-PPARα mice and that novel therapeutic strategies aimed at reducing CD36-mediated FA uptake show promise for the prevention or treatment of cardiac dysfunction related to obesity and diabetes.

Original languageEnglish (US)
Pages (from-to)1208-1217
Number of pages10
JournalCirculation research
Volume100
Issue number8
DOIs
StatePublished - Apr 2007

Keywords

  • Cardiomyopathy
  • Diabetes mellitus
  • Fatty acids
  • Glucose
  • Metabolism

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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