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

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

doi:10.1074/jbc.m111.296947

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.

Highlights

The importance of de novo ceramide biosynthesis in maintaining cardiac function is unknown
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
HSptlc2 KO mice did not show any significant changes in body weight, plasma glucose, TG, and cholesterol compared with control floxed mice

Summary

Background

The importance of de novo ceramide biosynthesis in maintaining cardiac function is unknown. FAs, especially saturated FAs, are converted to ceramide via a series of reactions mediated by serine palmitoyltransferase (SPT), 3-ketosphinganine reductase, ceramide synthase, and dihydroceramide desaturase This de novo sphingolipid biosynthetic pathway is activated in the setting of excess cellular palmitate [6] and is likely to be increased in the setting of obesity and diabetes. Since no significant reduction in ceramide levels in neurons is found with these defects, it suggests that there is a compensatory mechanism to maintain cellular ceramide when SPT function is reduced [15] It implies that some change other than ceramide deficiency such as sphingolipid composition is responsible for the neuropathy. We previously reported that the SPT inhibitor myriocin prevents cardiac toxicity associated with excess ceramide [18] This treatment reduced ceramide in lipotoxic hearts, it did not alter ceramide levels in normal hearts. We created mice with a cardiomyocyte-specific deficiency of Sptlc (hSptlc KO), to test whether SPT deficiency alters heart ceramide levels and/or affects the metabolism of other heart lipids

EXPERIMENTAL PROCEDURES

RESULTS

DISCUSSION