Straight-chain acyl-CoA oxidase knockout mouse accumulates extremely long chain fatty acids from alpha-linolenic acid: evidence for runaway carousel-type enzyme kinetics in peroxisomal beta-oxidation diseases.

[neonatal adrenoleukodystrophy]

Extremely long chain polyunsaturated fatty acids (ELCPs ) with >24 carbons and four or more double bonds are normally found in excitatory tissues but have no known function , and are greatly increased in brain and other tissues of humans with peroxisomal disorders . Straight-chain acyl-CoA oxidase (AOX ) catalyzes the first , rate-limiting step of peroxisomal beta -oxidation of very -long -chain saturated and unsaturated fatty acids . We have studied the polyunsaturated fatty acid metabolism of AOX knockout mice (AOX-/- as a model of human AOX deficiency (pseudo-neonatal adrenoleukodystrophy ), and as a genetic tool to test the putative peroxisomal beta -oxidation involvement in polyunsaturated fatty acid synthesis . Liver lipids of 26 -day -old weanling AOX-/- mice livers accumulate n-3 and n-6 ELCPs from C 2 4 to C 3 0 with 5 and 6 double bonds , have 356 +/- 66 microg /g docosahexaenoic acid (22 :6 n-3 ), similar to congenic (AOX -/* = AOX +/+ and AOX +/-) controls (401 +/- 96 microg /g ), but increased 22 :5 n-6 (22 .4 +/- 3 .7 vs 6 .4 +/- 1 .5 microg /g ). AOX +/* mice injected intraperitoneally at 23 days with [U-(13 )C ]-18 :3 n-3 show strong labeling of 22 :6 n-3 after 72 h , whereas AOX -/- mice display less labeling of 22 :6 n-3 but strong tracer incorporation into 24 :6 n-3 , 26 :6 n-3 , and 28 :6 n-3 , after the same period . These data suggest that ELCPs are natural runaway elongation by -products of 22 :6 n-3 and 22 :5 n-6 synthesis , which are normally disposed of by peroxisomal beta -oxidation . Under conditions with impaired peroxisomal beta -oxidation , such as Zellweger syndrome and adrenoleukodystrophies , ELCPs accumulate due to increased synthesis and impaired disposal . Two mechanisms for the formation of these runaway elongation by -products and the involvement of secondary carnitine deficiency in this process are proposed : n-3 ELCPs are synthesized by a carnitine-dependent multifunctional mitochondrial docosahexaenoic acid synthase (mtDHAS ) which normally synthesizes primarily 22 :6 n-3 , while n-6 ELCPs are synthesized by independent elongation enzymes in the endoplasmic reticulum .