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
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.
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.)