Cited by 246Peroxisome Proliferator-Activated ReceptorsCardiovascular Function and Risk FactorsCardiovascular Disease and Adiposity

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CD36 Deficiency Rescues Lipotoxic Cardiomyopathy

Yang, John, Sambandam, Nandakumar, Han, Xianlin, Gross, Richard W., Courtois, Michael, Kovacs, Attila, Febbraio, Maria, Finck, Brian N., Kelly, Daniel P.·2007·Circulation Research

DOI 10.1161/01.res.0000264104.25265.b6

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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.

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Authors: Yang, J., Sambandam, N., Han, X., Gross, R. W., Courtois, M., Kovacs, A., Febbraio, M., Finck, B. N., & Kelly, D. P.
Affiliations: Cleveland Clinic (US)
From the Center for Cardiovascular Research (J.Y., N.S., R.W.G., M.C., A.K., D.P.K.) and Departments of Medicine (J.Y., N.S., X.H., R.W.G., M.C., A.K., B.N.F., D.P.K.), Molecular Biology & Pharmacology (R.W.G., D.P.K.), and Pediatrics (D.P.K.), Washington University School of Medicine, St Louis, Mo; and Department of Cell Biology (M.F.), Lerner Research Institute, Cleveland Clinic, Ohio.
ORCID: Han, Xianlin
Gross, Richard W.
Febbraio, Maria
Finck, Brian N.
Kelly, Daniel P.
Venue: Circulation Research
Publisher: Ovid Technologies (Wolters Kluwer Health)
Published: 2007-04-27
Volume: 100
Issue: 8
Pages: 1208-1217
ISSN: 0009-7330 (ISSN-L)
1524-4571
DOI: 10.1161/01.res.0000264104.25265.b6
OpenAlex: W2160476964
Cited by: 246
References: 57
Citations by year: 2026: 5 · 2025: 8 · 2024: 10 · 2023: 5 · 2022: 11 · 2021: 13 · 2020: 13 · 2019: 7 · 2018: 18 · 2017: 12 · 2016: 16 · 2015: 14 · 2014: 11 · 2013: 12 · 2012: 22
FWCI: 7.41
Type: journal article
Language: en
Open access: closed
Locations: Circulation Research (publishedVersion)
PubMed (publishedVersion)
Funders: National Heart, Lung, and Blood Institute (P01HL57278, P01HL057278, P50HL077113, K08HL076452, KO8 HL076452)
National Institute of Diabetes and Digestive and Kidney Diseases (P30 DK-52574, P30-DK56341, P30DK056341, P30DK052574)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Function and Risk Factors
Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Disease and Adiposity
Keywords: CD36, lipotoxic cardiomyopathy, PPARα, fatty acid uptake, cardiac dysfunction, triglyceride accumulation, glucose uptake, glucose oxidation, fatty acid oxidation, obesity, diabetes mellitus, myosin heavy chain, high-fat diet, myocardial lipid metabolism
MeSH terms: Animals, Diabetic Angiopathies, Fatty Acids, Glucose, Mice, Inbred C57BL, Mice, Transgenic, Obesity, Oxidation-Reduction, Phenotype, Mice, Knockout, CD36 Antigens, PPAR alpha, Adiposity, Mice

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CD36 Deficiency Rescues Lipotoxic Cardiomyopathy

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