title: Cardiomyocyte specific deficiency of serine palmitoyltransferase subunit 2 reduces ceramide but leads to cardiac dysfunction.
abstract: 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.
authors.affiliation: Department of Life Science, Gachon University, Seongnam-Si, Gyeonggi-Do, Republic of Korea.
authors.forename: Su-Yeon
authors.initials: SY
authors.lastname: Lee
authors.forename: Jung Ran
authors.initials: JR
authors.lastname: Kim
authors.forename: Yunying
authors.initials: Y
authors.lastname: Hu
authors.forename: Raffay
authors.initials: R
authors.lastname: Khan
authors.forename: Su-Jung
authors.initials: SJ
authors.lastname: Kim
authors.forename: Kalyani G
authors.initials: KG
authors.lastname: Bharadwaj
authors.forename: Mercy M
authors.initials: MM
authors.lastname: Davidson
authors.forename: Cheol-Soo
authors.initials: CS
authors.lastname: Choi
authors.forename: Kyong-Oh
authors.initials: KO
authors.lastname: Shin
authors.forename: Yong-Moon
authors.initials: YM
authors.lastname: Lee
authors.forename: Woo-Jin
authors.initials: WJ
authors.lastname: Park
authors.forename: In-Sun
authors.initials: IS
authors.lastname: Park
authors.forename: Xian-Cheng
authors.initials: XC
authors.lastname: Jiang
authors.forename: Ira J
authors.initials: IJ
authors.lastname: Goldberg
authors.forename: Tae-Sik
authors.initials: TS
authors.lastname: Park
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D015153:Blotting, Western; D002478:Cells, Cultured; D002518:Ceramides / Q000378:metabolism*; D006321:Heart / Q000503:physiopathology*; D020287:In Situ Nick-End Labeling; D008055:Lipids / Q000097:blood; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009206:Myocardium / Q000201:enzymology*; D051102:Serine C-Palmitoyltransferase / Q000235:genetics / Q000378:metabolism*
chemical_list: D001786:Blood Glucose; D002518:Ceramides; D008055:Lipids; D051102:Serine C-Palmitoyltransferase