Nervonic acid: Source, production, and biological functions

Introduction

Nervonic acid is a long chain unsaturated fatty acid and a monounsaturated analog of lignoceric acid. It is also called cis-15-tetracosenoic acid and selacholeic acid. It composes of choline, phosphoric acid, sphingosine, and fatty acid. It is found as an elongation product of oleic acid and its immediate precursor is being erucic acid. Particularly it is abundant in white matter of animal brains and in peripheral nervous tissues where nervonyl sphingolipids are embellished in myelin sheath of nerve fibers. It is a critical member of cerebrosides group which are fatty acids of glycophingolipids group, an important component of muscles and central nervous system and peripheral.

Sources

Nervonic acid is synthesized from the carbon chain elongation of oleic acid (C18:1 ω-9), in which two C units donated by malonyl-CoA are cyclically added to the acyl chain. The cycle occurs at the endoplasmic reticulum membrane, where four steps are included. 3-Ketoacyl-CoA synthase (KCS) catalyzes the condensation of long-chain acyl-CoA with malonyl-CoA, and the produced 3-oxoacyl-CoA is converted to 3-hydroxyacyl-CoA with the reduction by 3-ketoacyl-CoA reductase. Then, the action of 3-hydroxacyl-CoA dehydratase results in the generation of 2-enoyl-CoA. Finally, an elongated acyl-CoA is formed after 2-enoyl-CoA is reduced by trans-2,3-enoyl-CoA reductase. KCS exhibits high substrate-specific properties, whereas the three other enzymes involved in this process function in all tissues and possess broad substrate specificity. Thus, KCS is the rate-limiting enzyme of the Nervonic acid biosynthesis pathway.[1]

Separation and purification

Nervonic acid can be isolated and purified by crystallization from mixed fatty acids on the basis of the different solubility and temperature dependence of the mixture in a solvent. The performance is mainly affected by solvent types. The recovery and purity of Nervonic acid product are also subjected to other factors, such as material-to-solvent ratio, cooling crystallization temperature, and cooling crystallization speed. The sodium salt–ethanol system converts mixed fatty acids into fatty acid salts via saponification. The difference in solubility of different fatty acid metal salts in organic solvent is conducive for Nervonic acid separation, and acidification is subsequently applied. The merits of economy, high yield, and good removal of low carbonated fatty acids elevate the feasibility of metal salt precipitation.[2]

Molecular distillation, which is also known as short-path distillation, is a special high-vacuum liquid–liquid separation technique according to the average distance of molecular freedom motion. The best solvent system for HPCC is a ternary solvent system consisting of n-hexane, ethanol, and water. The results indicate that a weakly polar solvent system is suitable because Nervonic acid is a weakly polar molecule. Urea adduction fractionation (UAF) is a simple method in separating fatty acids. Urea molecules are complexed with saturated fatty acids or monounsaturated fatty acids, thereby forming stable crystal inclusion, whereas unsaturated fatty acids are not easily included by urea because of the presence of double bonds and carbon chain bending. The amount of methyl-cis-15-tetracosenoate in A. truncatum increases from 5.48% to 17.10% after two times of urea inclusion treatment. Low processing temperature preserves the molecular structure, physicochemical properties, and physiological activity of Nervonic acid well. The equipment required for UAF is simple, and the reagents used are easy to obtain and can be recycled. These methods deliver good results in the separation and purification of Nervonic acid, whereas the characteristics of various extraction methods result in the differences in production yield, quality, and purity of Nervonic acid. Furthermore, the extraction processing method used in oil production is essential for Nervonic acid preservation. Ultrasonic circulating extraction is applied to samara oil production from Acer saccharum, and the yield of samara oil (11.72 ± 0.38%) and content of Nervonic acid (5.28 ± 0.18%) are achieved. Supercritical CO2 fluid extraction performs well through the optimization of M. oleifera oil extraction, and free Nervonic acid content can reach 5.4%.

Benefits to brain tissue

Dietary Nervonic acid or EA elevates the Nervonic acid proportion of sphingolipids in humans (Barre & Holub, 1992). Dietary Nervonic acid as a free fatty acid can cross the mammary epithelium and incorporate milk sphingomyelin. Subsequently, milk Nervonic acid is transferred across the intestinal epithelium and is accumulated in tissues of suckling rats. Dietary Nervonic acid supplied by T. speciosum oil extract (0.125 wt% in diet) improves the sphingomyelin Nervonic acid levels in the liver and heart, but the increase in brain sphingomyelin is not significant. Its bioavailability can be compared with that of 24:1n-9-ethyl. Therefore, Nervonic acid, including those in the form of triglycerides or sphingosine, may easily cross the intestinal tract and mammary epithelial barrier and accumulate in heart and liver tissues.

However, Nervonic acid present in triacylglycerol or its free state does not readily penetrate the blood brain and placental barriers. Dietary oil (Lunaria oil, 6.8% of Nervonic acid in the test diet), which is rich in Nervonic acid and erucic acids (EA, C22:1), causes normal Nervonic acid level in the brain sphingomyelin of homozygous quaking mice that are characterized by the deficient myelination of the central nervous system. However, the effect is maintained for only up to 2 weeks postbirth in nonmyelinated brain cells because dietary Nervonic acid in the blood is unavailable to the brain because it can no longer cross the blood–brain barrier.

Alzheimer's disease, psychosis, and depressive disorder

Serum fatty acid composition and erythrocyte membrane phospholipid can be an accessible indicator of fatty acids in the nervous system, neuronal membranes, and brain phospholipids (Assies et al., 2001, Song et al., 2018). Accordingly, an investigation and analysis focused on the cognitive impairment of the elderly aged ≥60 years and older and their serum fatty acid profile. The study found that the risk of Alzheimer's disease (AD) decreases with increasing serum Nervonic acid levels and increases with decreasing eicosenoic acid levels. However, some studies reported conflicting findings. Abnormalities in brain sphingolipid metabolism have an implication on age-related neurodegeneration. Elevated stearoyl-CoA desaturase (SCD), along with Nervonic acid levels, is associated with AD. Prominently increased Nervonic acid-containing sphingolipids and SCD in the hippocampus of old male and female mice indicate the possible contribution of these factors to age-dependent disorders. The pathogenesis of AD affected by Nervonic acid remains unclear.

Prodromal symptoms of psychosis have confirmed their close relation with decreased Nervonic acid levels in erythrocyte membranes. Furthermore, decreased Nervonic acid levels are observed in the red blood cells of patients with psychosis. Conversely, Nervonic acid levels are also evidently high in psychotic patients and their unaffected siblings. The contradiction may be due to different disease groups, periods of onset, drug use, and living environments. Johanna et al. reported that the Nervonic acid levels in the plasma and erythrocytes of patients with recurrent depression are significantly lower than those in normal people. Conflicting results showed that increased plasma Nervonic acid levels may be a potential biomarker for major depressive disorder assessment. The inconsistency may be attributed to the differences in subtypes of major depressive disorder (recurrent vs. nonrecurrent).[3]

References

[1] Li, Q., Chen, J., Yu, X., & Gao, J.-M. (2019). A mini review of nervonic acid: Source, production, and biological functions. Food Chemistry, 301, 125286.

[2] Lin, X., Wang, J., & Wu, J. (2008). Physicochemical properties of Vitex negundo seed oil and the isolation of its nervonic acid. China Oils and Fats, 33(10), 37–39.

[3] Kageyama, Y., Kasahara, T., Nakamura, T., Hattori, K., Deguchi, Y., Tani, M., & Kato, T. (2018). Plasma nervonic acid is a potential biomarker for major depressive disorder: A pilot study. International Journal of Neuropsychopharmacology, 21(3), 207–215.

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