CD36 deficiency rescues lipotoxic cardiomyopathy

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 alpha (PPAR alpha), is sufficient to drive the metabolic and functional abnormalities of the diabetic heart. Mice with cardiac-restricted overexpression of PPAR alpha ( myosin heavy chain [MHC]-PPAR alpha) 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-PPAR alpha mice were crossed with CD36-deficient mice (MHC-PPAR alpha/CD36(-/-) mice). The absence of CD36 prevented myocyte triacylglyceride accumulation and cardiac dysfunction in the MHC-PPAR alpha mice under basal conditions and following administration of high-fat diet. Surprisingly, the rescue of the MHC-PPAR alpha 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 PPAR alpha target genes involved in myocardial FA-oxidation pathways in the hearts of the MHC-PPAR alpha mice was unchanged in the CD36-deficient background. However, PPAR alpha-mediated suppression of genes involved in glucose uptake and oxidation was reversed in the MHC-PPAR alpha/ CD36(-/-) mice. We conclude that CD36 is necessary for the development of lipotoxic cardiomyopathy in MHC-PPAR alpha 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.