Metabolic fate of docosahexaenoic acid (DHA; 22:6n-3) in human cells: direct retroconversion of DHA to eicosapentaenoic acid (20:5n-3) dominates over elongation to tetracosahexaenoic acid (24:6n-3)

Docosahexaenoic acid (22:6n-3) supplementation in humans causes eicosapentaenoic acid (20:5n-3) levels to rise in plasma, but not in neural tissue where 22:6n-3 is the major omega-3 in phospholipids. We determined whether neuronal cells (Y79 and SK-N-SH) metabolize 22:6n-3 differently from non-neuronal cells (MCF7 and HepG2). We observed that (13) C-labeled 22:6n-3 was primarily esterified into cell lipids. We also observed that retroconversion of 22:6n-3 to 20:5n-3 was 5- to 6-fold greater in non-neural compared to neural cells and that retroconversion predominated over elongation to tetracosahexaenoic acid (24:6n-3) by 2-5-fold. The putative metabolic intermediates, (13) C-labeled 22:5n-3 and (13) C-labeled 24:5n-3, were not detected in our assays. Analysis of the expression of enzymes involved in fatty acid beta-oxidation revealed that MCF7 cells abundantly expressed the mitochondrial enzymes CPT1A, ECI1, and DECR1, whereas the peroxisomal enzyme ACOX1 was abundant in HepG2 cells, thus suggesting that the initial site of 22:6n-3 oxidation depends on the cell type. Our data reveal that non-neural cells more actively metabolize 22:6n-3 to 20:5n-3 via channeled retroconversion, while neural cells retain 22:6n-3.