Identification of a fatty acid Δ⁶-desaturase deficiency in human skin fibroblasts

Polyunsaturated fatty acid (PUFA) utilization was investigated in skin fibroblasts cultured from a female patient with an inherited abnormality in lipid metabolism. These deficient human skin fibroblasts (DF) converted 85-95% less [1-¹⁴C]linoleic acid (18:2n-6) to arachidonic acid (20:4n-6), 95% less [3-¹⁴C]tetracosatetraenoic acid (24:4n-6) to docosapentaenoic acid (22:5n-6), and 95% less [1-¹⁴C]linolenic acid (18:3n-3) and [3-¹⁴C]tetracosapentaenoic acid (24:5n-3) to docosahexaenoic acid (22:6n-3) than did normal human skin fibroblasts (NF). The only product formed by the DF cultures from [1-¹⁴C]tetradecadienoic acid (14:2n-6) was 18:2n-6. However, they produced 50-90% as much 20:4n-6 as the NF cultures from [1-¹⁴C] hexadecatrienoic acid (16:3n-6), [1-¹⁴C]γ-linolenic acid (18:3n-6), and [1-¹⁴C]dihomo-γ-linolenic acid (20:3n-6), PUFA substrates that contain Δ⁶ double bonds. DF also contained 80% more 18:2n-6 and 25% less 20:4n-6. These results suggested that DF are deficient in Δ⁶ desaturation. This was confirmed by Northern blots demonstrating an 81-94% decrease in Δ⁶desaturase mRNA content in the DF cultures, whereas the Δ⁵-desaturase mRNA content was reduced by only 14%. This is the first inherited abnormality in human PUFA metabolism shown to be associated with a Δ⁶-desaturase deficiency. Furthermore, the finding that the 18- and 24-carbon substrates are equally affected suggests that a single enzyme carries out both Δ⁶ desaturation reactions in human PUFA metabolism.