Identification of a fatty acid delta6-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% le...

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Bibliographic Details
Published in:Journal of lipid research 2001-04, Vol.42 (4), p.501-508
Main Authors: Williard, D E, Nwankwo, J O, Kaduce, T L, Harmon, S D, Irons, M, Moser, H W, Raymond, G V, Spector, A A
Format: Article
Language:English
Subjects:
Cells, Cultured
Child
Chromatography, High Pressure Liquid
Dietary Fats - administration & dosage
Fatty Acid Desaturases - deficiency
Fatty Acid Desaturases - genetics
Fatty Acid Desaturases - metabolism
Fatty Acids, Omega-3 - metabolism
Fatty Acids, Omega-6
Fatty Acids, Unsaturated - metabolism
Female
Fibroblasts - enzymology
Fibroblasts - metabolism
Humans
Linoleoyl-CoA Desaturase
Lipid Metabolism, Inborn Errors - enzymology
RNA, Messenger - genetics
RNA, Messenger - metabolism
Skin - cytology
Skin - enzymology
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Summary: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]gamma-linolenic acid (18:3n-6), and [1-14C]dihomo-gamma-linolenic acid (20:3n-6), PUFA substrates that contain Delta6 double bonds. DF also contained 80% more 18:2n-6 and 25% less 20:4n-6. These results suggested that DF are deficient in Delta6 desaturation. This was confirmed by Northern blots demonstrating an 81;-94% decrease in Delta6-desaturase mRNA content in the DF cultures, whereas the Delta5-desaturase mRNA content was reduced by only 14%. This is the first inherited abnormality in human PUFA metabolism shown to be associated with a Delta6-desaturase deficiency. Furthermore, the finding that the 18- and 24-carbon substrates are equally affected suggests that a single enzyme carries out both Delta6 desaturation reactions in human PUFA metabolism.
ISSN:0022-2275