Quantitation of alpha-linolenic acid elongation to eicosapentaenoic and docosahexaenoic acid as affected by the ratio of n6/n3 fatty acids.

Conversion of linoleic acid (LA) and alpha-linolenic acid (ALA) to their higher chain homologues in humans depends on the ratio of ingested n6 and n3 fatty acids. In order to determine the most effective ratio with regard to the conversion of ALA to eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), human hepatoma cells were incubated with varying ratios of [¹³C] labeled linoleic acid ([¹³C]LA)- and alpha-linolenic acid ([¹³C]ALA)-methylesters. Regulative cellular signal transduction pathways involved were studied by determinations of transcript levels of the genes encoding delta-5 desaturase (D5D) and delta-6 desaturase (D6D), peroxisome proliferator-activated receptor alpha (PPARα) and sterol regulatory element binding protein 1c (SREBP-1c). Mitogen-activated protein kinase kinase 1 (MEK1) and mitogen-activated protein kinase kinase kinase 1 (MEKK1) were also examined. Maximum conversion was observed in cells incubated with the mixture of [¹³C]LA/[¹³C]ALA at a ratio of 1:1, where 0.7% and 17% of the recovered [¹³C]ALA was converted to DHA and EPA, respectively. Furthermore, differential regulation of enzymes involved in the conversion at the transcript level, dependent on the ratio of administered n6 to n3 fatty acids in human hepatocytes was demonstrated. Formation of EPA and DHA was highest at an administered LA/ALA ratio of 1:1, although gene expression of PPARα, SREBP-1c and D5D involved in ALA elongation were higher in the presence of ALA solely. Also, our findings suggest that a diet-induced enhancement of the cell membrane content of highly unsaturated fatty acids is only possible up to a certain level.