Cardiomyocyte Specific Deficiency of Serine Palmitoyltransferase Subunit 2 Reduces Ceramide but Leads to Cardiac Dysfunction

• Published in: The Journal of biological chemistry 2012-05, Vol.287 (22), p.18429-18439
• Main Authors: Lee, Su-Yeon, Kim, Jung Ran, Hu, Yunying, Khan, Raffay, Kim, Su-Jung, Bharadwaj, Kalyani G., Davidson, Mercy M., Choi, Cheol-Soo, Shin, Kyong-Oh, Lee, Yong-Moon, Park, Woo-Jin, Park, In-Sun, Jiang, Xian-Cheng, Goldberg, Ira J., Park, Tae-Sik
• Format: Article
• Language: English
• Subjects: Animals; Blood Glucose - metabolism; Blotting, Western; Cells, Cultured; Ceramide; Ceramides - metabolism; Fatty Acid; Heart - physiopathology; Heart Failure; In Situ Nick-End Labeling; Lipids; Lipids - blood; Mice; Mice, Inbred C57BL; Mice, Knockout; Myocardium - enzymology; Phospholipid; Serine C-Palmitoyltransferase - genetics; Serine C-Palmitoyltransferase - metabolism; Sphingolipid
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M111.296947

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. The importance of de novo ceramide biosynthesis in maintaining cardiac function is unknown. Deletion of serine palmitoyltransferase subunit Sptlc2 reduced cardiac ceramide and caused cardiac dysfunction associated with activation of ER stress. Reduced ceramide content by Sptlc2 deficiency does not protect against lipid toxicity associated with increased saturated acyl CoAs. Development of disease by lipotoxicity is caused by a number of changes in lipidome.