Metabolism and Supply of Polyunsaturated Fatty Acids to Brain Capillary Endothelial Cells

The brain is highly enriched in the long-chain PUFAs such as DHA (22:6w-3) and arachidonic acid (20:4w-6). In particular, DHA is the most abundant w-3 fatty acid in the brain. These PUFAs can be synthesized from fatty acid precursors linoleic acid (18:2w-6) and linolenic acid (LA,18:3w-3) through a process of fatty-acid chain elongation and desaturation. By contrast to the PUFAs, their respective precursors, linoleic acids and LA, are present at only low levels in the brain. The liver is a major site where shorter-chain dietary PUFA is converted to arachi-donic acid and DHA, although some retinal and cerebral cells, such as retinal pigment epithelial cells and astrocytes, have the ability to produce DHA. Moreover, low levels of DHA and several of its w-3 PUFA precursors normally are present in the plasma, and all of these substrates can be utilized in the brain. The brain capillary endothelial cells are thought to take up PUFA precursors and target them preferentially into the brain, performing some elongation and desaturation in the process. In rats, after incubation of cultured brain endothelial cells with [3—14C] docosapen-taenoic acid (22:5w-3) in the presence of serum, radioactivity is primarily recovered in eicosapentaenoic acid (EPA, 20:5w-3); however, DHA, 24:5w-3, and 24:6w-3 were also labeled. Therefore, brain ECs can synthesize and secrete DHA and it 24-C precursors. In addition, one study demonstrated that mouse cerebral endothelium converted 18:3 w-3 into 22:5w-3, but could not accomplish the last desaturation. The brain capillary ECs are highly enriched in DHA and arachidonic acid and important for the supply of nutrients to the brain, but it is thought that ECs do not play a major role in DHA synthesis. On the other hand, it has been demonstrated that rat astrocytes appear to be a major site for DHA and arachidonic acid synthesis. Indeed, astrocytes, not neurons, elongated and desaturated the 18- and 20-carbon precursors and released DHA and arachidonic acid into the culture medium. It has also been shown that the amount of DHA synthesis from w-3 PUFA precursors in astrocytes may be regulated by the availability of DHA or other PUFA in the brain tissue or cerebral circulation. Furthermore, in vitro data indicate that DHA synthesis from w-3 PUFA precursors takes place primarily in astrocytes and that these cells supply some of the newly formed DHA to the neurons and BBB endothelium. In order to examine the participation of astrocytes in this synthesis, cocultures of endothelial cell and astrocytes mimicking the in vivo BBB were used. Endothelial cells cultured alone weakly converted the precursor fatty acids into 20:4w-6 and 22:6w-3. Astrocytes play a major role in the delivery of essential PUFAs to the barrier itself and to the brain. It was discovered based on experiments using cocultures of astrocytes and ECs that astrocytes synthesize DHA from w-3 PUFA precursors and contribute to the ability of brain ECs in the reconstituted BBB to synthesize DHA and arachidonic acid from their 18-carbon precursors. When endothelial cells were cocultured with astrocytes, their content of PUFA increased dramatically. These fatty acids were released by astrocytes after they were synthesized from the precursor fatty acids that passed through the endothelial cell monolayer into the astrocyte medium. Astrocytes play an important role in the brain by elongation of free fatty acids and desaturation action of w-3 and w-6 of fatty acid precursors of arachidonic acids and DHA. Astrocytes may thereafter complete the conversion of precursors to DHA, releasing it for uptake by neurons and brain ECs. Studies of cultured cells suggest that astrocytes are the main site of DHA and arachidonic acid synthesis in the brain. Astrocytes may contribute positively to the high level of fatty acid desaturation necessary for capillary endothelial cell functions such as those carried out in the BBB.

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