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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2004;24:943.)
© 2004 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Ceramide Synthesis Correlates with the Posttranscriptional Regulation of the Sterol-Regulatory Element-Binding Protein

Tilla S. Worgall; Rebecca A. Juliano; Toru Seo; Richard J. Deckelbaum

From the Department of Pathology (T.S.W.), Institute of Human Nutrition (T.S.W., R.A.J., T.S., R.J.D.), and Department of Pediatrics (R.J.D.), Columbia University, New York, NY.

Correspondence to Dr Tilla S. Worgall, Columbia University, 630 W 168th Street, PH 1512, New York, NY 10032. E-mail tpw7{at}columbia.edu

Objective— Sterol-regulatory element-binding proteins (SREBPs) regulate transcription of genes of lipid metabolism. Ceramide decreases transcriptionally active SREBP levels independently of intracellular cholesterol levels. Mechanisms of the ceramide-mediated decrease of SREBP levels were investigated.

Methods and Results— Experiments were performed in Chinese hamster ovary cells. Inhibition of ceramide synthesis with myriocin, cycloserine, or fumonisin decreases levels of transcriptionally active SREBP and reduces SRE-mediated gene transcription. When ceramide synthesis is increased through exogenous sphingosine or inhibition of sphingosine kinase, SRE-mediated gene transcription is increased. The important role of ceramide synthesis in SRE-mediated gene transcription is confirmed in LY-B cells that do not synthesize ceramide de novo. LY-B cells fail to increase SRE-mediated gene transcription in sterol depletion.

Conclusions— Ceramide synthesis correlates with the generation of transcriptionally active SREBP and SRE-mediated gene transcription. Inhibition of ceramide synthesis decreases levels of transcriptionally active SREBP and SRE-mediated gene transcription. It is hypothesized that the process of ongoing ceramide synthesis contributes to the physiological processing of SREBP, perhaps affecting ER-to-Golgi trafficking. Taken together, modification of ceramide synthesis could be a novel target for drug development in the pharmacologic modification of SRE-dependent pathways.

Key Words: SREBP • ceramide • myriocin • LY-Bsphingosine

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