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

Background: Docosahexaenoic acid (DHA, 22:6 omega 3) 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 Delta 4-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. Results: We showed that the Delta 4-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, Delta 4-desaturase) by producing DHA from direct Delta 4-desaturation of 22:5 omega 3. We also found that the other substrate for Delta 4-desaturase, 22:4 omega 6, was parallely desaturated to 22:5 omega 6. Conclusions: The present in vitro study demonstrates that Delta 4-desaturase can be transfected into human cells and synthesize DHA (as well as 22:5 omega 6, DPA) from 22:5 omega 3 and 22:4 omega 6, respectively, by putative Delta 4-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.