The synthesis of phosphatidylcholine (PtdCho) by the CDP-choline pathway is under the control of the rate-limiting enzyme CTP:phosphocholine cytidylyltransferase (CCT). Sterol regulatory element binding proteins (SREBPs) have been proposed to regulate CCT at the transcriptional level, or via the synthesis of lipid activators or substrates of the CDP-choline pathway. To assess the contributions of these two mechanisms, we examined CCTα expression and PtdCho synthesis by the CDP-choline pathway in cholesterol and fatty acid auxotrophic CHO M19 cells inducibly expressing constitutively active nuclear forms of SREBP1a or SREBP2. Induction of either SREBP resulted in increased expression of mRNAs for sterol-regulated genes, elevated fatty acid and cholesterol synthesis (>10–50-fold) and increased PtdCho synthesis (2-fold). CCTα mRNA was increased 2-fold by enforced expression of SREBP1a or SREBP2. The resultant increase in CCTα protein and activity (2-fold) was restricted primarily to the soluble fraction of cells, and increased CCTα activity in vivo was not detected. Inhibition of the synthesis of fatty acids or their CoA esters by cerulenin or triacsin C respectively following SREBP induction effectively blocked the accompanying elevation in PtdCho synthesis. Thus PtdCho synthesis was driven by increased synthesis of fatty acids or a product thereof. These data show that transcriptional activation of CCTα is modest relative to that of other SREBP-regulated genes, and that stimulation of PtdCho synthesis by SREBPs in CHO cells is due primarily to increased fatty acid synthesis.
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June 2003
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Research Article|
June 15 2003
Regulation of the CDP-choline pathway by sterol regulatory element binding proteins involves transcriptional and post-transcriptional mechanisms
Neale D. RIDGWAY;
Neale D. RIDGWAY
1
Departments of Pediatrics, and Biochemistry and Molecular Biology, Atlantic Research Center, Dalhousie University, Halifax, Nova Scotia, Canada B3H 3H7
1To whom correspondence should be addressed (e-mail nridgway@dal.ca).
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Thomas A. LAGACE
Thomas A. LAGACE
Departments of Pediatrics, and Biochemistry and Molecular Biology, Atlantic Research Center, Dalhousie University, Halifax, Nova Scotia, Canada B3H 3H7
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Publisher: Portland Press Ltd
Received:
February 12 2003
Revision Received:
March 21 2003
Accepted:
March 26 2003
Accepted Manuscript online:
March 26 2003
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London ©2003
2003
Biochem J (2003) 372 (3): 811–819.
Article history
Received:
February 12 2003
Revision Received:
March 21 2003
Accepted:
March 26 2003
Accepted Manuscript online:
March 26 2003
Citation
Neale D. RIDGWAY, Thomas A. LAGACE; Regulation of the CDP-choline pathway by sterol regulatory element binding proteins involves transcriptional and post-transcriptional mechanisms. Biochem J 15 June 2003; 372 (3): 811–819. doi: https://doi.org/10.1042/bj20030252
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