Zellweger syndrome knockout mouse models challenge putative peroxisomal beta-oxidation involvement in docosahexaenoic acid (22 : 6n-3) biosynthesis

The putative involvement of peroxisomal beta -oxidation in the biosynthetic pathway of docosahexaenoic acid (22:6n-3, DHA) synthesis is critically rev iewed in light of experiments with two recently developed knockout mouse mo dels for Zellweger syndrome, a peroxisomal disorder affecting brain develop ment. These mice were generated by targeted disruption of the PEX2 and PEX5 peroxisomal assembly genes encoding targeting signal receptor peroxins for the recognition and transport of a set of peroxisomal enzymes, including t hose of peroxisomal p-oxidation, to the peroxisomal matrix. Analysis of est erified 22:6n-3 concentrations in PEX2(-/-) and PEX5(-/-) mice do not suppo rt the hypothesized requirement of peroxisomal beta -oxidation in 22:6n-3 s ynthesis, as only brain, but not liver or plasma, 22:6n-3 levels were decre ased. Supplementation of PEX5(+/-) darns with 22:6n-3, although restoring t he levels of brain 22:6n-3 in total lipids to that of controls, did not nor malize the phenotype. These decreased brain 22:6n-3 concentrations appear t o be secondary to impaired plasmalogen (sn-1-alkyl-, alkenyl-2-acyl glycero phospholipids) synthesis, probably at the level of the dihydroxyacetonephos phate acyltransferase (DHAP-AT), a peroxisomal enzyme catalyzing the first step in the synthesis of 22:6n-3-rich plasmalogens. To diminish the confoun ding effects of impaired plasmalogen synthesis in the brains of these Zellw eger syndrome mouse models, kinetic experiments with labeled precursors, su ch as 18:3n-3 or 20:5n-3, in liver or isolated hepatocytes, which have negl igible amounts of plasmalogens, are suggested to establish the rates of 22: 6n-3 biosynthesis and precursor-product relationships. Similar experiments using brain of the acyl-CoA oxidase knockout mouse model are proposed to co nfirm the lack of peroxisomal beta -oxidation involvement in 22:6n-3 synthe sis, since this mutation would not impair plasmalogen synthesis. (C) 2001 A cademic Press.