Submitted on March 24, 2008
Revised on May 20, 2008
Accepted on May 29, 2008
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
Medicine, Columbia University, New York, NY 10032
Corresponding Author: 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 (LpLGPI). 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 LpLGPI hearts, improved systolic function and prolonged survival rates. Our results suggest a critical role for ceramide accumulation in the pathogenesis of lipotoxic cardiomyopathy.
CiteULike 
Complore 
Connotea 
Del.icio.us 
Digg 
Reddit 
Technorati What's this?