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

Abstract

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 Δ6-desaturase 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. —Williard, D. E., J. O. Nwankwo, T. L. Kaduce, S. D. Harmon, M. Irons, H. W. Moser, G. V. Raymond, and A. A. Spector. Identification of a fatty acid Δ6-desaturase deficiency in human skin fibroblasts. J. Lipid Res. 2001. 42: 501–508.

Keywords

• polyunsaturated fatty acids
• fatty acid desaturation
• Δ5-desaturase
• linoleic acid
• α-linolenic acid
• arachidonic acid