, Volume 40, Issue 7, pp 719-728

Changes of the transcriptional and fatty acid profiles in response to n−3 fatty acids in SH-SY5Y neuroblastoma cells

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Synthesis of docosahexaenoic acid (DHA) from its metabolic precursors contributes to membrane incorporation of this FA within the central nervous system. Although cultured neural cells are able to produce DHA, the membrane DHA contents resulting from metabolic conversion do not match the high values of those resulting from supplementation with preformed DHA. We have examined whether the DHA precursors downregulate the incorporation of newly formed DHA within human neuroblastoma cells. SH-SY5Y cells were incubated with gradual doses of α-linolenic acid (α-LNA), EPA, or docosapentaenoic acid (DPA), and the incorporation of DHA into ethanolamine glycerophospholipids was analyzed as a reflection of synthesizing activity. The incorporation of EPA, DPA, and preformed DHA followed a dose-response saturating curve, whereas that of DHA synthesized either from α-LNA, EPA, or DPA peaked at concentrations of precursors below 15–30 μM and sharply decreased with higher doses. The mRNA encoding for six FA metabolism genes were quantified using real-time PCR. Two enzymes of the peroxisomal β-oxidation, L-bifunctional protein and peroxisomal acyl-CoA oxidase, were expressed at lower levels than fatty acyl-CoA ligase 3 (FACL3) and Δ6-desaturase (Δ6-D). The Δ6-D mRNA slightly increased between 16 and 48 h of culture, and this effect was abolished in the presence of 70 μM EPA. In contrast, the EPA treatment resulted in a time-dependent increase of FACL3 mRNA. The terminal step of DHA synthesis seems to form a “metabolic bottleneck,” resulting in accretion of EPA and DPA when the precursor concentration exceeds a specific threshold value. We conclude that the critical precursor-concentration window of responsiveness may originate from the low basal expression level of peroxisomal enzymes.