December 2010

[JLR] Complex Inter-regulation of the Cers

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Biobits - ceramide

Small interfering RNA-mediated knockdown of CerS2 (left) and CerS6 (right) cause a shift in the expression of nontargeted CerS proteins.

Although several types of sphingolipids exist within a cell, they all share a common backbone— ceramide. To date, six enzymes, named ceramide synthases, have been identified as responsible for producing Cer. In this study, researchers examined how individual CerS proteins maintain and regulate the cellular pool of Cer species and other sphingolipids, using small interfering RNAs to decrease the expression of CerS1-6 in a human adenocarcinoma cell line, MCF-7. The knockdown of individual CerS proteins resulted in increased expression of nontargeted CerS proteins and shifted the profile of Cer and other sphingolipid species but did not decrease the total level of sphingolipids. When multiple CerS proteins were knocked down simultaneously, the total level of Cer did not change but caused upregulation of other sphingolipids that are associated with other sphingolipid metabolism pathways as well as increased ER stress responses. Together, these data suggest that Cer synthesis is regulated highly and maintained through the redundant and counter-regulatory network of CerS-mediated synthesis— a finding that provides more insight into the complexities of lipid biosynthesis.

Selective Knockdown of Ceramide Synthases Reveals Complex Inter-regulation of Sphingolipid Metabolism

Thomas D. Mullen, Stefka Spassieva, Russell W. Jenkinds, Kazuyuki Kitatani, Jacek Bielawski, Yusuf A. Hannun and Lina M. Obeid

J. Lipid. Res., published online Oct. 11, 2010

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