Genetic And Dietary Factors Which Influence N3 Fatty Acid Metabolism

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Because of the inability to synthesize n-3 fatty acids de novo, all animals require these fatty acids in their diet to meet their demand for maintaining a high concentration of DHA in the brain. Although little direct evidence exists in any species concerning the quantitative conversion of n-3 fatty acid precursors to DHA, it has been estimated based on rodent studies that an n-3 fatty acid intake of 0.5% of energy as a-linolenic acid (LNA) is needed in order to maintain an adequate level of DHA in the brain (Bourre et al., 1989). However, it must be recognized that the ability to biosynthesize DHA from LNA or other n-3 fatty acids varies among different animal species (Rivers et al., 1975; Hassam et al., 1977; Sinclair et al., 1979; Clandinin et al., 1985; Scott & Bazan, 1989: Salem & Pawlosky, 1994; Pawlosky et al., 1994: Fu & Sinclair, 2000). Moreover, the composition of fat in the diet has a significant influence on the liver production of long-chain PUFAs (Salem & Pawlosky, 1994; Pawlosky et al., 1994). For instance, it was observed that when nonhuman primates were fed a diet that contained relatively low levels of long-chain PUFAs (where eicosapentaeonic acid [EPA] and DHA were present at a level of 0.54% and 0.64% of the total dietary fat, respectively) the formation of labeled-DHA from labeled-LNA was inhibited in the liver (Pawlosky & Salem, 1993). However, both arachidonic acid (AA) (from labeled-LA) and docosapentaenoic acid (DPAn-3) were synthesized in the liver and detected in the blood of the same animals on this diet. When animals were then placed on a diet devoid of long-chain PUFAs, the synthesis of DHA was observed in the liver, and labeled-DHA was detected in the blood after 3 wk. This strongly suggests that the conversion of DPAn-3 to DHA in the liver is partly controlled by the concentration of DHA in the diet. It is interesting to theorize whether the regulation of the biosynthesis of DHA from DPAn-3 is maintained at the level of transcription of a A-6 desaturase which is needed to catalyze the conversion of 24:5n3 to 24:6n-3 (Marzo et al., 1996). If so, this form of regulation would have the advantage of selectively controlling DHA production, yet it would not necessarily inhibit the synthesis of other long-chain PUFAs (e.g., arachidonic acid).

Because of the genetic and dietary factors, which are capable of controlling and influencing the production of long-chain PUFAs, different species have developed various independent strategies for obtaining DHA. In the cat family, for instance, preformed DHA in the diet appears to be necessary to maintain a high concentration of DHA in the CNS (Pawlosky et al., 1997). The need for preformed DHA in the diet is probably caused by a low PUFA biosynthetic capability of this species (Hassam, 1977; Rivers, 1975; Sinclair, 1979) as well as an inherent inability to produce DHA in the feline liver (Pawlosky et al., 1994). However, there is increasing evidence that suggests that the production of DHA from LNA may be a highly inefficient process in other species, as well (Menard et al., 1998; Su et al., 1999). Nevertheless, it appears that the majority of species (other than members of the cat family) have some capacity to biosynthesize DHA from LNA in their livers.

Although, the liver has long been recognized as an important site of PUFA biosynthesis (Buzzi et al., 1997; Clandinin et al., 1985; Pawlosky et al., 1992; Schenck et al, 1996), a number of animal studies in various species have shown that long-chain PUFAs (in particular, 22:6n-3) can be synthesized by different components of the nervous system (Dhopeswarkar et al., 1974; Clandinin et al., 1985; Delton-Vandenbrouke et. al, 1997; Chen et. al, 1999; Moore, 1993; Moore et al., 1991; Pawlosky et al., 1994; Pawlosky et al., 1996; Protstein, 1996). The cells of the nervous system, like other cells of the body, take up DHA and other n-3 fatty acids from lipoproteins that are carried in the blood. There is evidence that the preferred form of DHA for uptake into the brain is as a lyso-phospholipid rather than as a free fatty acid (Bernoud et al., 1999). This route may offer an efficient transfer of DHA into the neuron for phospholipid synthesis and membrane biogenesis. Although felines are the only species in which it has been demonstrated that the entire brain accretion of biosynthesized DHA is the result of production that occurs within the CNS (Pawlosky et al., 1994) other species carry on similar intra-CNS processes to obtain at least part of their DHA (Pawlosky et al., 1996). Figure 1 depicts a representation of the feline strategy for the accretion of DHA in brain. From dietary sources, LNA or EPA is taken up into the liver where the fatty acids are converted into DPAn-3. DPAn-3 is released from the liver and carried on lipoproteins to the CNS, where it is converted to DHA. There is similar evidence from other species that have shown that brain cells (Moore et al., 1991) or cells isolated from the cerebral vasculature (Delton-Vandenbroucke et al., 1997) are capable of biosynthesizing DHA from n-3 fatty acid precursors.

Several investigators have described plausible mechanisms for the production of DHA in the CNS. Moore and co-workers described the biosynthesis of DHA and transport of fatty acids through microcapillary cerebral endothelial cells, astrocytes, and neurons (Moore et al., 1991; Moore, 1993). In this model, microcapillary endothelial cells produce DPAn-3 from LNA, which is turned over to the astrocytes to be synthesized into DHA. The astrocytes then release DHA, which is taken up by neurons. In contrast, Delton-Vandenbroucke and co-workers found that cerebral vascular cells produced appreciable amounts of labeled-DHA from DPAn-3 (Delton-Vandenbroucke et al., 1997). They theorize that cerebral endothelial cells will convert circulating DPAn-3 into DHA, which is then taken up into the brain. These reports suggest that in the CNS, unlike the liver in which biosynthesis of DHA from LNA takes place entirely within the hepatocyte,

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Fig. 1. A schematic representation of the biosynthesis and accretion of DHA into the CNS of felines. Dietary n-3 fatty acids (LNA) are taken up into the liver and synthesized into DPAn-3 (22:5n-3). DPAn-3 is released from the liver and carried on lipoproteins in the blood to the nervous system. The synthesis of DHA is completed in the brain from DPAn-3.

Fig. 1. A schematic representation of the biosynthesis and accretion of DHA into the CNS of felines. Dietary n-3 fatty acids (LNA) are taken up into the liver and synthesized into DPAn-3 (22:5n-3). DPAn-3 is released from the liver and carried on lipoproteins in the blood to the nervous system. The synthesis of DHA is completed in the brain from DPAn-3.

more than a single cell type (either an astrocyte or endothelial cell) may act in a synergistic fashion to contribute to the synthesis and accretion of DHA.

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