Ceramide is a cardiotoxin in lipotoxic cardiomyopathy.
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.
Division of Preventive Medicine and Nutrition, Department of Medicine, Columbia University, College of Physicians and Surgeons, New York, NY 10032, USA.
Tae-Sik
TS
Park
Yunying
Y
Hu
Hye-Lim
HL
Noh
Konstantinos
K
Drosatos
Kazue
K
Okajima
Jonathan
J
Buchanan
Joseph
J
Tuinei
Shunichi
S
Homma
Xian-Cheng
XC
Jiang
E Dale
ED
Abel
Ira J
IJ
Goldberg
D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002311:Cardiomyopathy, Dilated / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D054715:Cardiotoxins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002417:Cattle; D002518:Ceramides / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005227:Fatty Acids / Q000378:metabolism; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology; D017353:Gene Deletion; D005786:Gene Expression Regulation / Q000187:drug effects; D005947:Glucose / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D017261:Glycosylphosphatidylinositols / Q000378:metabolism; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D006333:Heart Failure / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D008071:Lipoprotein Lipase / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D010084:Oxidation-Reduction; D010766:Phosphorylation / Q000187:drug effects; D051102:Serine C-Palmitoyltransferase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015996:Survival Rate
D015415:Biomarkers; D054715:Cardiotoxins; D002518:Ceramides; D005227:Fatty Acids; D005229:Fatty Acids, Monounsaturated; D017261:Glycosylphosphatidylinositols; D051102:Serine C-Palmitoyltransferase; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3; D008071:Lipoprotein Lipase; D005947:Glucose; C001996:thermozymocidin