Abstract
DHA (C22:6n-3) is an important PUFA implicated in a number of (patho)physiological processes. For a long time, the exact mechanism of DHA formation has remained unclear, but now it is known that it involves the production of tetracosahexaenoic acid (C24:6n-3) from dietary linolenic acid (C18:3n-3) via a series of elongation and desaturation reactions, followed by beta-oxidation of C24:6n-3 to C22:6n-3. Although DHA is deficient in patients lacking peroxisomes, the intracellular site of retroconversion of C24:6n-3 has remained controversial. By making use of fibroblasts from patients with defined mitochondrial and peroxisomal fatty acid oxidation defects, we show in this article that peroxisomes, and not mitochondria, are involved in DHA formation by catalyzing the beta-oxidation of C24:6n-3 to C22:6n-3. Additional studies of fibroblasts from patients with X-linked adrenoleukodystrophy, straight-chain acyl-CoA oxidase (SCOX) deficiency, d-bifunctional protein (DBP) deficiency, and rhizomelic chondrodysplasia punctata type 1, and of fibroblasts from l-bifunctional protein and sterol carrier protein X (SCPx) knockout mice, show that the main enzymes involved in beta-oxidation of C24:6n-3 to C22:6n-3 are SCOX, DBP, and both 3-ketoacyl-CoA thiolase and SCPx. These findings are of importance for the treatment of patients with a defect in peroxisomal beta-oxidation.
Highlights
IntroductionDHA (C22:6n-3) is an important PUFA implicated in a number of (patho)physiological processes
DHA (C22:6n-3) is an important PUFA implicated in a number ofphysiological processes
To elucidate the role of both the peroxisome and mitochondrion, we studied the biosynthesis of DHA from [1-14C]18:3n-3, [1-14C]20:5n-3, and [3-14C]24:6n-3 in fibroblasts from patients with a peroxisome biogenesis disorder and from patients with a deficiency of one of the following mitochondrial enzymes: carnitine palmitoyltransferase 1 (CPT1), carnitine acylcarnitine translocase (CACT), carnitine palmitoyltransferase 2 (CPT2), and very long-chain acyl-CoA dehydrogenase (VLCAD)
Summary
DHA (C22:6n-3) is an important PUFA implicated in a number of (patho)physiological processes. The exact mechanism of DHA formation has remained unclear, but it is known that it involves the production of tetracosahexaenoic acid (C24:6n-3) from dietary linolenic acid (C18:3n-3) via a series of elongation and desaturation reactions, followed by -oxidation of C24:6n-3 to C22:6n-3. The -oxidation step in the revised pathway of PUFA biosynthesis requires a considerable exchange of unsaturated fatty acids between different subcellular compartments [6]. DHA (C22:6n-3), the major PUFA in adult mammalian brain and retina, was believed to be synthesized from dietary linolenic acid (C18:3n-3) in a pathway consisting of a series of elongation and desaturation reactions.
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