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J Biol Chem, Vol. 275, Issue 19, 14367-14374, May 12, 2000
From the Atlantic Research Center and the Departments of Pediatrics
and Biochemistry and Molecular Biology, Dalhousie University,
Halifax, Nova Scotia B3H 4H7, Canada
Sterol regulation-defective (SRD) 4 cells
expressing a mutant sterol regulatory element-binding protein (SREBP)
cleavage-activating protein (SCAP D443N) and Chinese hamster ovary
(CHO) cells stably expressing SCAP (CHO-SCAP) and SCAP D443N
(CHO-SCAP-D443N) have increased cholesterol and fatty acid synthesis
because of constitutive processing of SREBPs. We assessed whether
constitutive activation of SREBPs also influenced the CDP-choline
pathway for phosphatidylcholine (PtdCho) biosynthesis. Relative to
control CHO 7 cells, SRD 4 cells displayed increased PtdCho synthesis
and degradation as indicated by a 4-6-fold increase in
[3H]choline incorporation into PtdCho and
10-15-fold increase in intracellular
[3H]glycerophosphocholine.
[3H]Phosphocholine levels in SRD 4 cells were reduced by
over 10-fold, suggesting enhanced activity of CTP:phosphocholine
cytidylyltransferase
Regulation of Phosphatidylcholine Metabolism in Chinese
Hamster Ovary Cells by the Sterol Regulatory Element-binding Protein
(SREBP)/SREBP Cleavage-activating Protein Pathway*
, and
(CCT). CHO-SCAP and CHO-SCAP D443N cells
displayed modest increases in [3H]choline incorporation
into PtdCho (2-fold) and only a 2-fold reduction in
[3H]phosphocholine. Elevated PtdCho metabolism in SRD 4, compared with SCAP-overexpressing cells, was correlated with fatty acid synthesis. Inhibition of fatty acid synthesis by cerulenin resulted in
almost complete normalization of PtdCho synthesis and choline metabolite profiles in SRD 4 cells, indicating that fatty acids or a
fatty acid-derived metabolite was responsible for up-regulation of
PtdCho synthesis. In contrast to apparent activation in
vivo, CCT protein, mRNA, and in vitro activity
were reduced in SRD 4 cells and unchanged in SCAP transfected cells.
Unlike control and SCAP transfected cells, CCT in SRD 4 cells was
localized by immunofluorescence to the nuclear envelope, suggesting
that residual enzyme activity in these cells was in an active
membrane-associated form. Translocation of CCT to the nuclear
envelope was reproduced by treatment of CHO 7 cells with exogenous
oleate. We conclude that the SREBP/SCAP pathway regulates PtdCho
synthesis via post-transcriptional activation of nuclear CCT by
fatty acids or a fatty acid-derived signal.
*
This work was support by a program grant from the Medical
Research Council of Canada.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Present address: National Jewish Medical and Research Center,
Dept. of Medicine, 1400 Jackson St., Denver, CO 80206.
§
To whom correspondence should be addressed: Atlantic Research
Center, Rm. C306, Clinical Research Center, 5849 University Ave.,
Dalhousie University, Halifax, Nova Scotia B3H 4H7, Canada. Tel.:
902-494-7133; Fax: 902-494-1394; E-mail: nridgway@is.dal.ca.
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