The zellweger syndrome: Deficient conversion of docosahexaenoic acid (22:6( n−3)) to eicosapentaenoic acid (20:5( n−3)) and normal Δ 4-desaturase activity in cultured skin fibroblasts

Abstract

The metabolism of docosahexaenoic acid (22:6( n−3))and adrenic acid (22:4( n−6)) was studied in cultured fibroblasts from patients with the Zellweger syndrome, X-linked adrenoleukodystrophy (X-ALD) and normal controls. It was shown that [4,5- 3H] 22:6( n−3) is retroconverted to labelled eicosapentaenoic acid (20:5( n−3)) in normal and X-ALD fibroblasts, while this conversion is deficient in Zellweger fibroblasts. [U- 14C]Eicosapentaenoic acid (20:5( n−3)) is elongated to docosapentaenoic acid (22:5( n−3))in all three cell lines. With [U- 14C]20:5( n−3) as the substrate, shorter fatty acids were not detected. With [4,5- 3H]22:6( n−3) as the substrate, labelled fatty acids were esterified in the phospholipid- and triacylglycerol-fraction to approximately the same extent in all three cell lines. [2- 14C]Adrenic acid (22:4( n−6)) was desaturated to 22:5( n−6) and elongated to 24:4( n−6) in all three cell lines and to the largest extent in the Zellweger fibroblasts. This agrees with the view that the Δ 4-desaturase is not a peroxisomal enzyme. The observation that the retroconversion of 22:6( n−3) to 20:5( n−3) is deficient in Zellweger fibroblasts strongly suggest that the β-oxidation step in the retroconversion is a peroxisomal function. Peroxisomal very-long-chain (lignoceryl) CoA ligase is probably not required for the activation of 22:6( n−3), since the retroconversion to 20:5( n−3) is normal in X-ALD fibroblasts.