Docosahexaenoic acid (DHA) is important for brain function, and can be obtained directly from the diet or synthesized in the body from α-linolenic acid (ALA). Debate exists as to whether DHA synthesized from ALA can provide sufficient DHA for the adult brain, as measures of DHA synthesis from ingested ALA are typically <1% of the oral ALA dose. However, the primary fate of orally administered ALA is β-oxidation and long-term storage in adipose tissue, suggesting that DHA synthesis measures involving oral ALA tracer ingestion may underestimate total DHA synthesis. There is also evidence that DHA synthesized from ALA can meet brain DHA requirements, as animals fed ALA-only diets have brain DHA concentrations similar to DHA-fed animals, and the brain DHA requirement is estimated to be only 2.4-3.8 mg/day in humans. This review summarizes evidence that DHA synthesis from ALA can provide sufficient DHA for the adult brain by examining work in humans and animals involving estimates of DHA synthesis and brain DHA requirements. Also, an update on methods to measure DHA synthesis in humans is presented highlighting a novel approach involving steady-state infusion of stable isotope-labeled ALA that bypasses several limitations of oral tracer ingestion. It is shown that this method produces estimates of DHA synthesis that are at least 3-fold higher than brain uptake rates in rats.

Despite being critical for normal brain function, the pools that supply docosahexaenoic acid (DHA) to the brain are not agreed upon. Using multiple kinetic models in free-living adult rats, we first demonstrate that DHA uptake from the plasma non-esterified fatty acid (NEFA) pool predicts brain uptake of DHA upon oral administration, which enters the plasma NEFA pool as well as multiple plasma esterified pools. The rate of DHA loss by the brain is similar to the uptake from the plasma NEFA pool. Furthermore, upon acute iv administration, although more radiolabeled lysophosphatidylcholine (LPC)-DHA enters the brain than NEFA-DHA, this is due to the longer plasma half-life and exposure to the brain. Direct comparison of the uptake rate of LPC-DHA and NEFA-DHA demonstrates that uptake of NEFA-DHA into the brain is 10-fold greater than LPC-DHA. In conclusion, plasma NEFA-DHA is the major plasma pool supplying the brain.

Observational evidence suggests that in populations consuming low levels of n-3 highly unsaturated fatty acids, women have higher blood levels of docosahexaenoic acid (DHA; 22:3n-6) as compared with men. Increased conversion of alpha-linolenic acid (ALA; 18:3n-3) to DHA by females has been confirmed in fatty acid stable isotope studies. This difference in conversion appears to be associated with estrogen and some evidence indicates that the expression of enzymes involved in synthesis of DHA from ALA, including desaturases and elongases, is elevated in females. An estrogen-associated effect may be mediated by peroxisome proliferator activated receptor-alpha (PPARalpha), as activation of this nuclear receptor increases the expression of these enzymes. However, because estrogens are weak ligands for PPARalpha, estrogen-mediated increases in PPARalpha activity likely occur through an indirect mechanism involving membrane-bound estrogen receptors and estrogen-sensitive G-proteins. The protein kinases activated by these receptors phosphorylate and increase the activity of PPARalpha, as well as phospholipase A(2) and cyclooxygenase 2 that increase the intracellular concentration of PPARalpha ligands. This review will outline current knowledge regarding elevated DHA production in females, as well as highlight interactions between estrogen signaling and PPARalpha activity that may mediate this effect.

Tracer studies suggest that phospholipid DHA (PL-DHA) more effectively targets the brain than triglyceride DHA (TAG-DHA), although the mechanism and whether this translates into higher brain DHA concentrations are not clear. Rats were gavaged with [U-(3)H]PL-DHA and [U-(3)H]TAG-DHA and blood sampled over 6h prior to collection of brain regions and other tissues. In another experiment, rats were supplemented for 4weeks with TAG-DHA (fish oil), PL-DHA (roe PL) or a mixture of both for comparison to a low-omega-3 diet. Brain regions and other tissues were collected, and blood was sampled weekly. DHA accretion rates were estimated using the balance method. [U-(3)H]PL-DHA rats had higher radioactivity in cerebellum, hippocampus and remainder of brain, with no differences in other tissues despite higher serum lipid radioactivity in [U-(3)H]TAG-DHA rats. TAG-DHA, PL-DHA or a mixture were equally effective at increasing brain DHA. There were no differences between DHA-supplemented groups in brain region, whole-body, or tissue DHA accretion rates except heart and serum TAG where the PL-DHA/TAG-DHA blend was higher than TAG-DHA. Apparent DHA β-oxidation was not different between DHA-supplemented groups. This indicates that more labeled DHA enters the brain when consumed as PL; however, this may not translate into higher brain DHA concentrations.

Docosahexaenoic acid (DHA, 22:6n-3) is higher in the blood and tissues of females relative to males, but the underlying mechanism is not clear. The present study examined the expression of enzymes involved in the biosynthesis of DHA from short-chain n-3 polyunsaturated fatty acids in male and female rats (n = 6 for each sex). Rats were maintained on an AIN-93G diet and sacrificed at 14 weeks of age after an overnight fast. Plasma, erythrocytes, liver, heart, and brain were collected for fatty acid composition analysis and the determination of enzyme and transcription factor expression by RT-PCR and immunoblotting. Females had higher DHA concentrations in the total lipids of liver, plasma, erythrocyte, and heart (53%, 75%, 36%, and 25% higher, respectively, compared with males) with no sex differences in brain DHA concentrations. The mRNA content of Δ5-desaturase, Δ6-desaturase, and elongase 2 was 1.0-, 1.4-, and 1.1-fold higher, respectively, in the livers of female rats compared with males, with no differences in the hearts or brains. The protein content of Δ6-desaturase was also higher in females. Higher hepatic mRNA of sterol-regulatory element-binding protein 1-c and estrogen receptor α in the females suggests that lipogenic and estrogen signaling mechanisms are involved. The sex difference in DHA concentration is tissue specific and is associated with higher Δ6-desaturase expression in females relative to males, which appears to be limited to the liver.

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Linoleic acid (LA; 18:2 n-6), the most abundant polyunsaturated fatty acid in the US diet, is a precursor to oxidized metabolites that have unknown roles in the brain. Here, we show that oxidized LA-derived metabolites accumulate in several rat brain regions during CO2-induced ischemia and that LA-derived 13-hydroxyoctadecadienoic acid, but not LA, increase somatic paired-pulse facilitation in rat hippocampus by 80%, suggesting bioactivity. This study provides new evidence that LA participates in the response to ischemia-induced brain injury through oxidized metabolites that regulate neurotransmission. Targeting this pathway may be therapeutically relevant for ischemia-related conditions such as stroke.

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