Ceramide is a cardiotoxin in lipotoxic cardiomyopathy

被引：320

作者：

Park, Tae-Sik ^{[1
,3
]}

Hu, Yunying ^{[1
]}

Noh, Hye-Lim ^{[1
]}

Drosatos, Konstantinos ^{[1
]}

Okajima, Kazue ^{[2
]}

Buchanan, Jonathan ^{[4
,5
]}

Tuinei, Joseph ^{[4
,5
]}

Homma, Shunichi ^{[2
]}

Jiang, Xian-Cheng ^{[6
]}

Abel, E. Dale ^{[4
,5
]}

Goldberg, Ira J. ^{[1
]}

机构：

[1] Columbia Univ, Coll Phys & Surg, Dept Med, Div Prevent Med & Nutr, New York, NY 10032 USA

[2] Columbia Univ, Coll Phys & Surg, Dept Med, Div Cardiol, New York, NY 10032 USA

[3] Gachon Univ Med & Sci, Lee Gil Ya Canc & Diabet Inst, Inchon, South Korea

[4] Univ Utah, Sch Med, Program Human Mol Biol & Genet, Salt Lake City, UT 84112 USA

[5] Univ Utah, Sch Med, Div Endocrinol Metab & Diabet, Salt Lake City, UT 84112 USA

[6] Suny Downstate Med Ctr, Dept Anat & Cell Biol, Brooklyn, NY 11203 USA

来源：

JOURNAL OF LIPID RESEARCH | 2008年 / 49卷 / 10期

基金：

美国国家卫生研究院;

关键词：

serine palmitoyltransferase; lipotoxicity; heart; glucose; fatty acid;

D O I：

10.1194/jlr.M800147-JLR200

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：2101 / 2112

页数：12

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