Novel Metabolism of Docosahexaenoic Acid in Neural Cells

Introduction

Long-chain polyunsaturated fatty acids are highly enriched in the nervous system. Docosahexaenoic acid (DHA; 22:6n-3),in particular, is the most abundant polyunsaturated fatty acid in the brain and is concentrated in aminophospholipids of cell membranes. Numerous studies have indicated that this concentration of DHA in the nervous system is essential for optimal neuronal and retinal functions (1).

Although the underlying mechanisms of its essential function are still not clearly understood, emerging evidence suggests that unique metabolism of DHA in relation to its incorporation into neuronal membrane phospholipids plays an important role. In this review, biochemical mechanisms for enriching and metabolizing DHA in neural cells are discussed in the context of their biological significance in neuronal function.

Published May 8, 2007 by Hee-Yong Kim

From the Laboratory of Molecular Signaling, Division of Intramural Clinical and Biological Research, National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland 20892-9410

Conclusion

Through specific accumulation and metabolic mechanisms operating in neural cells, DHA influences signaling events that are vital to neuronal survival and differentiation, as depicted in Fig. 3. DHA, supplied from the blood stream or biosynthesized in astroglia, is provided to neurons and rapidly incorporated into membrane phospholipids. Incorporation of DHA results in increased PS levels in neurons because of preferred PS synthesis from DHA-containing phospholipid substrates. The biochemical function of DHA in promoting PS accumulation in neuronal membranes is an important underpinning of the maintenance of neuronal survival. Specifically, Akt and Raf-1 translocation/activation is facilitated by the high concentration of PS in neuronal membranes. PS-dependent acceleration of Akt translocation is particularly important under suboptimal conditions, where the generation of survival signals such as PIP3 is limited. The Raf-1 translocation facilitated by DHA may contribute to neuronal differentiation, which is one of the downstream events of Raf-1 activation. The trophic action of DHA as a free fatty acid may also be important for neuronal differentiation, because DHA has been shown to be an endogenous ligand for the retinoid X receptor, a nuclear receptor that acts as a ligand-activated transcription factor. Transformation of DHA to NPD1 is protective, rescuing neuronal cells from cell death under pathological conditions. In conclusion, neuronal accretion of DHA and PS during development is required to prevent inappropriate cell death and to support neuronal differentiation. The loss of DHA and PS, or interference in their accumulation by nutritional deprivation or in pathological states, may diminish protective capacity in the central nervous system, with significant implications for neuronal dysfunction. Because PS-dependent signaling is a target for the neurotrophic action of DHA, it is important to understand the nature of specific regulation in neuronal PS accumulation. The metabolic regulation at both lipid and protein levels and post-translational modifications of PSS as well as the presence of other serine base exchange enzymes, which are specific to the brain, need to be explored further. Elucidating the molecular mechanisms underlying the protein interaction with DHA-containing phospholipids, as well as identifying new target signaling proteins and metabolites involved in DHA protection, is another fruitful area for future research.

(BTW, Last time I checked, Dr. Ritch also recommends pure DHA supplements. Maybe we could find out from him why he recommends DHA instead of EPA + DHA.)