Regulation of n-3 PUFA biosynthesis in proliferating and differentiated PC12 pheochromocytoma cells

Msika, Ora (2012) Regulation of n-3 PUFA biosynthesis in proliferating and differentiated PC12 pheochromocytoma cells. Doctoral thesis, London Metropolitan University.


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 (EPG) and phosphatidylserine (SPG) 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 similarly converted to 22:5n-3 and 22:6n-3. On the other hand, supplements of linoleic acid (LA, 18:2n-6) were not effectively converted into higher n-6 PUFA intermediates nor did they impair elongation/desaturation of ALA. 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 LA. NGF alters differently the expression of several genes involved in the FA metabolism; ElovJ5, EJovJ2, Fads2 and Ppara genes encoding, respectively, for ELOVL5 elongase, ELOVL2 elongase, Delta6 desaturase (D6D) and the nuclear transcription factor PPARa. LA up-regulates the expression of the above genes, whereas ALA specifically up-regUlates the mRNA levels of Fads2 and Elovl5. The results found in this thesis emphasise 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.

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