The Δ4-desaturation pathway for DHA biosynthesis is operative in the human species: Differences between normal controls and children with the Zellweger syndrome

Abstract

BackgroundDocosahexaenoic acid (DHA, 22:6ω3) is a fundamental component of cell membranes, especially in the brain and retina. In the experimental animal, DHA deficiency leads to suboptimal neurological performance and visual deficiencies. Children with the Zellweger syndrome (ZS) have a profound DHA deficiency and symptoms that can be attributed to their extremely low DHA levels. These children seem to have a metabolic defect in DHA biosynthesis, which has never been totally elucidated. Treatment with DHA ethyl ester greatly improves these patients, but if we could normalize their endogenous DHA production we could get additional benefits. We examined whether DHA biosynthesis by Δ4-desaturation could be enhanced in the human species by transfecting the enzyme, and if this could normalize the DHA levels in cells from ZS patients.ResultsWe showed that the Δ4-desaturase gene (Fad4) from Thraustochytrium sp, which can be expressed by heterologous transfection in other plant and yeast cells, can also be transfected into human lymphocytes, and that it expresses the enzyme (FAD4, Δ4-desaturase) by producing DHA from direct Δ4-desaturation of 22:5ω3. We also found that the other substrate for Δ4-desaturase, 22:4ω6, was parallely desaturated to 22:5ω6.ConclusionsThe present "in vitro" study demonstrates that Δ4-desaturase can be transfected into human cells and synthesize DHA (as well as 22:5ω6, DPA) from 22:5ω3 and 22:4ω6, respectively, by putative Δ4-desaturation. Even if this pathway may not be the physiological route for DHA biosynthesis "in vivo", the present study opens new perspectives for the treatment of patients within the ZS spectrum.

Profiling changes triggered during maturation of dendritic cells: a lipidomic approach

“…The cell culture procedure was designed to ensure that culture conditions in vitro are as close as possible to the in-vivo physiological microenvironment of cells. Nevertheless, it has been reported that fatty acid patterns are substantially altered when cell lines are immortalized [45] and in malignant cells [46]. The proportion of polyunsaturated fatty acid in both cases is much lower than in normal cells.…”

Plasmalogens the neglected regulatory and scavenging lipid species

“…Likewise transfection with Thraustochytrium sp. delta-4-desaturase (FAD4) was tested successfully in vitro as a future therapeutic option, although it does not represent the physiological pathway and the practical feasibility of this approach is not clear yet (Martinez et al, 2010).…”

Ether lipids

“…Depletion of plasmenyl-ethanolamine and DHA in brain characterizes patients suffering from Zellweger syndrome, leading to serious dysmyelination and multiple neurological abnormalities (Martinez and Mougan, 1999). DHA is an essential fatty acid in nervous tissue and retina, and is therefore implicated in normal brain and retina development, and in cognitive function (Martinez et al, 2010).…”