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Journal of Lipid Research, Vol. 42, 1266-1272, August 2001
Copyright © 2001 by Lipid Research, Inc.

Original Article

CTP:phosphocholine cytidylyltransferase, a new sterol- and SREBP-responsive gene

Correspondence to: Peter A. Edwards, at the Department of Biological Chemistry, CHS, 33-257 UCLA School of Medicine, Los Angeles, CA 90095-1769., pedwards{at}mednet.ucla.edu (E-mail)

The CTP:phosphocholine cytidylyltransferase (CT) gene encodes the rate-controlling enzyme in the phosphatidylcholine biosynthesis pathway. CT mRNA levels, like farnesyl diphosphate synthase and the LDL receptor, are repressed when human or rodent cells are incubated with exogenous sterols and induced when cells are incubated in lipid-depleted medium. A putative sterol response element (SRE) was identified 156 bp upstream of the transcription start site of the CT gene. Electrophoretic mobility shift assays demonstrate that recombinant SREBP-1a binds to the wild-type SRE identified in the CT promoter but not to oligonucleotides containing two mutations in the SRE. In other studies, a luciferase reporter construct under the control of the murine CT proximal promoter was transiently transfected into cells. The activity of the reporter was repressed after addition of sterols to the medium and induced when the cells were incubated in lipid-depleted medium. The activity of the CT-luciferase reporter was also induced when cells were cotransfected with plasmids encoding either SREBP-1a or SREBP-2. In contrast, no induction was observed under the same conditions when the CT promoter-reporter gene contained two mutations in the SRE. In addition, the induction of the wild-type CT promoter-reporter gene that occurs in cells incubated in lipid-depleted medium is attenuated when dominant-negative SREBP is cotransfected into the cells. These studies demonstrate that transcription of the CT gene is inhibited by sterols and activated by mature forms of SREBP.

We conclude that SREBP-regulated genes are involved not only in the synthesis of cholesterol, fatty acids, triglycerides, and NADPH, but also, as shown here, in the synthesis of phospholipids. — Kast, H. R., C. M. Nguyen, A. M. Anisfeld, J. Ericsson, and P. A. Edwards. CTP:phosphocholine cytidylyltransferase, a new sterol- and SREBP-responsive gene. J. Lipid Res. 2001. 42: 1266;–1272.

Supplementary key words: phosphatidylcholine, sterol response element, CT gene

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