Activity of the phosphatidylcholine biosynthetic pathway modulates the distribution of fatty acids into glycerolipids in proliferating cells.
PtdCho accumulation is a periodic, S phase-specific event that is modulated in part by cell cycle-dependent fluctuations in CTP:phosphocholine cytidylyltransferase (CCT) activity. A supply of fatty acids is essential to generate the diacylglycerol (DG) precursors for phosphatidylcholine (PtdCho) biosynthesis but it is not known whether the DG supply is also coupled to the cell cycle. Although the rate of fatty acid synthesis in a macrophage cell line was dramatically stimulated in response to the growth factor, CSF-1, it was not regulated by the cell cycle. Increased fatty acid synthesis correlated with elevated acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS) steady-state mRNA levels. Cellular fatty acid synthesis was essential for membrane PL synthesis. Cerulenin inhibition of endogenous fatty acid synthesis also inhibited PtdCho synthesis, which was not relieved by exogenous fatty acids. Inhibition of CCT activity by the addition of lysophosphatidylcholine (lysoPtdCho) or temperature-shift of a conditionally defective CCT diverted newly synthesized DG to the TG pool where it accumulated. Enforced expression of CCT stimulated PtdCho biosynthesis and reduced TG synthesis. Thus, the cellular DG supply did not regulate PtdCho biosynthesis and CCT activity governs the partitioning of DG into either the PL or TG pools, thereby controlling both PtdCho and TG biosynthesis.
Jackowski
S
S
Department of Biochemistry St. Jude Children's Research Hospital, 332 North Lauderdale, Memphis, TN 38105-2794, USA. suzanne.jackowski@stjude.org
Wang
J
J
Baburina
I
I
D000085:Acetates / Q000378:metabolism; D000103:Acetyl-CoA Carboxylase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000818:Animals; D016466:CHO Cells; D002453:Cell Cycle; D002460:Cell Line; D002569:Cerulenin / Q000494:pharmacology; D019916:Choline-Phosphate Cytidylyltransferase / Q000037:antagonists & inhibitors / Q000378:metabolism; D006224:Cricetinae; D004075:Diglycerides / Q000378:metabolism*; D064429:Fatty Acid Synthases / Q000235:genetics / Q000378:metabolism; D005227:Fatty Acids / Q000096:biosynthesis*; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D008934:Mitogens; D010713:Phosphatidylcholines / Q000096:biosynthesis*; D013696:Temperature; D014280:Triglycerides / Q000096:biosynthesis; D014316:Tritium
D000085:Acetates; D004075:Diglycerides; D005227:Fatty Acids; D008934:Mitogens; D010713:Phosphatidylcholines; D014280:Triglycerides; D014316:Tritium; D002569:Cerulenin; D016173:Macrophage Colony-Stimulating Factor; D064429:Fatty Acid Synthases; D019916:Choline-Phosphate Cytidylyltransferase; D000103:Acetyl-CoA Carboxylase