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% 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.
Williard
D E
DE
Department of Biochemistry, University of Iowa, Iowa City, IA 52242, USA.
Nwankwo
J O
JO
Kaduce
T L
TL
Harmon
S D
SD
Irons
M
M
Moser
H W
HW
Raymond
G V
GV
Spector
A A
AA
D002478:Cells, Cultured; D002648:Child; D002851:Chromatography, High Pressure Liquid; D004041:Dietary Fats / Q000008:administration & dosage; D044943:Fatty Acid Desaturases / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D015525:Fatty Acids, Omega-3 / Q000378:metabolism; D043371:Fatty Acids, Omega-6; D005231:Fatty Acids, Unsaturated / Q000378:metabolism*; D005260:Female; D005347:Fibroblasts / Q000201:enzymology* / Q000378:metabolism; D006801:Humans; D050602:Linoleoyl-CoA Desaturase; D008052:Lipid Metabolism, Inborn Errors / Q000201:enzymology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012867:Skin / Q000166:cytology / Q000201:enzymology
D004041:Dietary Fats; D015525:Fatty Acids, Omega-3; D043371:Fatty Acids, Omega-6; D005231:Fatty Acids, Unsaturated; D012333:RNA, Messenger; D044943:Fatty Acid Desaturases; D050602:Linoleoyl-CoA Desaturase; C094563:delta-15 desaturase