NGF blocks polyunsaturated fatty acids biosynthesis in n − 3 fatty acid-supplemented PC12 cells

Abstract

Regulation of polyunsaturated fatty acid (PUFA) biosynthesis in proliferating and NGF-differentiated PC12 pheochromocytoma cells deficient in n−3 docosahexaenoic acid (DHA 22:6n−3) was studied. A dose- and time-dependent increase in eicosapentaenoic acid (EPA, 20:5n−3), docosapentaenoic acid (DPA, 22:5n−3) and DHA in phosphatidylethanolamine (PtdEtn) and phosphatidylserine (PtdSer) glycerophospholipids (GPL) via the elongation/desaturation pathway following alpha-linolenic acid (ALA, 18:3n−3) supplements was observed. That was accompanied by a marked reduction of eicosatrienoic acid (Mead acid 20:3n−9), an index of PUFA deficiency. EPA supplements were equally effective converted to 22:5n−3 and 22:6n−3. On the other hand, supplements of linoleic acid (LNA, 18:2n−6) were not effectively converted into higher n−6 PUFA intermediates nor did they impair elongation/desaturation of ALA. Co-supplements of DHA along with ALA did not interfere with 20:5n−3 biosynthesis but reduced further elongation to 22-hydrocarbon PUFA intermediates. A marked decrease in the newly synthesized 22:5n−3 and 22:6n−3 following ALA or EPA supplements was observed after nerve growth factor (NGF)-induced differentiation. NGF also inhibited the last step in 22:5n−6 formation from LNA. These results emphasize the importance of overcoming n−3 PUFA deficiency and raise the possibility that growth factor regulation of the last step in PUFA biosynthesis may constitute an important feature of neuronal phenotype acquisition.