Document Detail

Cardiomyocyte specific deficiency of serine palmitoyltransferase subunit 2 reduces ceramide but leads to cardiac dysfunction.
MedLine Citation:
PMID:  22493506     Owner:  NLM     Status:  MEDLINE    
The role of serine palmitoyltransferase (SPT) and de novo ceramide biosynthesis in cardiac ceramide and sphingomyelin metabolism is unclear. To determine whether the de novo synthetic pathways, rather than ceramide uptake from circulating lipoproteins, is important for heart ceramide levels, we created cardiomyocyte-specific deficiency of Sptlc2, a subunit of SPT. Heart-specific Sptlc2-deficient (hSptlc2 KO) mice had a >35% reduction in ceramide, which was limited to C18:0 and very long chain ceramides. Sphingomyelinase expression, and levels of sphingomyelin and diacylglycerol were unchanged. But surprisingly phospholipids and acyl CoAs contained increased saturated long chain fatty acids. hSptlc2 KO mice had decreased fractional shortening and thinning of the cardiac wall. While the genes regulating glucose and fatty acid metabolism were not changed, expression of cardiac failure markers and the genes involved in the formation of extracellular matrices were up-regulated in hSptlc2 KO hearts. In addition, ER-stress markers were up-regulated leading to increased apoptosis. These results suggest that Sptlc2-mediated de novo ceramide synthesis is an essential source of C18:0 and very long chain, but not of shorter chain, ceramides in the heart. Changes in heart lipids other than ceramide levels lead to cardiac toxicity.
Su-Yeon Lee; Jung Ran Kim; Yunying Hu; Raffay Khan; Su-Jung Kim; Kalyani G Bharadwaj; Mercy M Davidson; Cheol-Soo Choi; Kyong-Oh Shin; Yong-Moon Lee; Woo-Jin Park; In-Sun Park; Xian-Cheng Jiang; Ira J Goldberg; Tae-Sik Park
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-04-09
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  287     ISSN:  1083-351X     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2012 May 
Date Detail:
Created Date:  2012-05-28     Completed Date:  2012-08-15     Revised Date:  2013-06-26    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  18429-39     Citation Subset:  IM    
Department of Life Science, Gachon University, Seongnam-Si, Gyeonggi-Do, Republic of Korea.
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MeSH Terms
Blood Glucose / metabolism
Blotting, Western
Cells, Cultured
Ceramides / metabolism*
Heart / physiopathology*
In Situ Nick-End Labeling
Lipids / blood
Mice, Inbred C57BL
Mice, Knockout
Myocardium / enzymology*
Serine C-Palmitoyltransferase / genetics,  metabolism*
Grant Support
Reg. No./Substance:
0/Blood Glucose; 0/Ceramides; 0/Lipids; EC C-Palmitoyltransferase

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