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; Ira J Goldberg

doi:10.1194/jlr.M800147-JLR200

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Ceramide is a cardiotoxin in lipotoxic cardiomyopathy

Journal article

Open access

Peer reviewed

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, …

Journal of lipid research, Vol.49(10), pp.2101-2112

10/2008

DOI: 10.1194/jlr.M800147-JLR200

PMCID: PMC2533410

PMID: 18515784

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Abstract

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.

Cardiomyopathy, Dilated - pathology

Fatty Acids, Monounsaturated - pharmacology

Humans

Heart Failure - physiopathology

Glycogen Synthase Kinase 3 beta

Serine C-Palmitoyltransferase - genetics

Cattle

Gene Deletion

Myocardium - metabolism

Cardiotoxins - antagonists & inhibitors

Phosphorylation - drug effects

Fatty Acids - metabolism

Lipoprotein Lipase - metabolism

Biomarkers - metabolism

Heart - physiopathology

Ceramides - metabolism

Oxidation-Reduction

Mice, Transgenic

Serine C-Palmitoyltransferase - antagonists & inhibitors

Survival Rate

Ceramides - antagonists & inhibitors

Heart Failure - metabolism

Heart Failure - pathology

Serine C-Palmitoyltransferase - metabolism

Glycogen Synthase Kinase 3 - metabolism

Cardiomyopathy, Dilated - metabolism

Gene Expression Regulation - drug effects

Animals

Myocytes, Cardiac - drug effects

Cardiomyopathy, Dilated - physiopathology

Glycosylphosphatidylinositols - metabolism

Glucose - metabolism

Heart - drug effects

Myocytes, Cardiac - metabolism

Mice

Cardiotoxins - metabolism

Details

Title: Subtitle: Ceramide is a cardiotoxin in lipotoxic cardiomyopathy
Creators: Tae-Sik Park - Division of Preventive Medicine and Nutrition, Department of Medicine, Columbia University, College of Physicians and Surgeons, New York, NY 10032, USA
Yunying Hu
Hye-Lim Noh
Konstantinos Drosatos
Kazue Okajima
Jonathan Buchanan
Joseph Tuinei
Shunichi Homma
Xian-Cheng Jiang
E Dale Abel
Ira J Goldberg
Resource Type: Journal article
Publication Details: Journal of lipid research, Vol.49(10), pp.2101-2112
DOI: 10.1194/jlr.M800147-JLR200
PMID: 18515784
PMCID: PMC2533410
NLM abbreviation: J Lipid Res
ISSN: 0022-2275
eISSN: 1539-7262
Publisher: United States
Grant note: U01 HL070525 / NHLBI NIH HHS R01 HL073029 / NHLBI NIH HHS HL-73167 / NHLBI NIH HHS HL-45095 / NHLBI NIH HHS HL-70525 / NHLBI NIH HHS HL-73029 / NHLBI NIH HHS R37 HL045095 / NHLBI NIH HHS R01 HL073167 / NHLBI NIH HHS R01 HL045095 / NHLBI NIH HHS
Language: English
Date published: 10/2008
Academic Unit: Roy J. Carver Department of Biomedical Engineering; Fraternal Order of Eagles Diabetes Research Center; Biochemistry and Molecular Biology; Endocrinology and Metabolism; Internal Medicine
Record Identifier: 9984024420702771

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