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Papers In Press, published online ahead of print October 1, 2008
J. Lipid Res., doi:10.1194/jlr.M800147-JLR200

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Journal of Lipid Research, Vol. 49, 2101-2112, October 2008
Copyright © 2008 by American Society for Biochemistry and Molecular Biology

Ceramide is a cardiotoxin in lipotoxic cardiomyopathy^*,

Tae-Sik Park^*,, Yunying Hu^*, Hye-Lim Noh^*, Konstantinos Drosatos^*, Kazue Okajima, Jonathan Buchanan^**, Joseph Tuinei^**, Shunichi Homma, Xian-Cheng Jiang, E. Dale Abel^** and Ira J. Goldberg^1,*

^* Division of Preventive Medicine and Nutrition, Department of Medicine, Columbia University, College of Physicians and Surgeons, New York, NY 10032
Division of Cardiology, Department of Medicine, Columbia University, College of Physicians and Surgeons, New York, NY 10032
Lee Gil Ya Cancer and Diabetes Institute, Gachon University of Medicine and Science, Inchon, South Korea
^** Program in Human Molecular Biology and Genetics and Division of Endocrinology, Metabolism, and Diabetes, University of Utah School of Medicine, Salt Lake City, UT 84112
Department of Anatomy and Cell Biology, SUNY Downstate Medical Center, Brooklyn, NY 11203

^* This study was supported by National Institutes of Health Grants HL-73029 and HL-45095 (T-S.P., I.J.G.), and HL-70525 and HL-73167 to E.D.A. from the National Heart, Lung, and Blood Institute.

The online version of this article (available at http://www.jlr.org) contains supplementary data in the form of two figures and one table.

Published, JLR Papers in Press, May 30, 2008.

¹ To whom correspondence should be addressed. e-mail: ijg3{at}columbia.edu

Ceramide is among a number of potential lipotoxic molecules that are thought to modulate cellular energy metabolism. The heart is one of the tissues thought to become dysfunctional due to excess lipid accumulation. Dilated lipotoxic cardiomyopathy, thought to be the result of diabetes and severe obesity, has been modeled in several genetically altered mice, including animals with cardiac-specific overexpression of glycosylphosphatidylinositol (GPI)-anchored human lipoprotein lipase (LpL^GPI). To test whether excess ceramide was implicated in cardiac lipotoxicity, de novo ceramide biosynthesis was inhibited pharmacologically by myriocin and genetically by heterozygous deletion of LCB1, a subunit of serine palmitoyltransferase (SPT). Inhibition of SPT, a rate-limiting enzyme in ceramide biosynthesis, reduced fatty acid and increased glucose oxidation in isolated perfused LpL^GPI hearts, improved systolic function, and prolonged survival rates. Our results suggest a critical role for ceramide accumulation in the pathogenesis of lipotoxic cardiomyopathy.

Supplementary key words serine palmitoyltransferase • lipotoxicity • heart • glucose • fatty acid

Abbreviations: DAG, diacylglycerol; 2-DG, 2-deoxy-D-glucose; GPI, glycosylphosphatidylinositol; LCB1^+/–, heterozygous LCB1 knockout; LVD, left ventricular systolic diameter; LpL, lipoprotein lipase; ROS, reactive oxygen species; SM, sphingomyelin; SPT, serine palmitoyltransferase; TG, triglyceride; WT, wild type

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