Food Chemistry 301 (2019) 125286

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Food Chemistry
journal homepage: www.elsevier.com/locate/foodchem

Review

A mini review of nervonic acid: Source, production, and biological functions T

a a a,⁎ b,⁎
Qi Li , Jia Chen , Xiuzhu Yu , Jin-Ming Gao
a
College of Food Science and Engineering, Northwest A&F University, 22 Xinong Road Yangling, 712100 Shaanxi, PR China
b
Shaanxi Key Laboratory of Natural Products & Chemical Biology, College of Chemistry & Pharmacy, Northwest A&F University, 22 Xinong Road Yangling, 712100
Shaanxi, PR China

A R T I C LE I N FO A B S T R A C T

Chemical compounds studied in this article: Nervonic acid (NA) has attracted considerable attention because of its close relationship with brain develop-
cis-15-Tetracosenoic acid (PubChem CID: ment. Sources of NA include oil crop seeds, oil-producing microalgae, and other microorganisms. Transgenic
5281120) technology has also been applied to improve the sources and production of NA. NA can be separated and purified
Methyl-cis-15-tetracosenoate (PubChem CID: by urea adduction fractionation, molecular distillation, and crystallization. Studies on NA functionality involved
5364841)
treatments for demyelinating diseases and acquired immunodeficiency syndrome, as well as prediction of
mortality due to cardiovascular diseases and chronic kidney disease. This mini review focuses on the sources,
Keywords:
production, and biological functions of NA and provides prospective trends in the investigation of NA.
Nervonic acid
Source
Production methods
Brain health

1. Introduction
Nervonic acid (C24:1 Δ15, cis-15-tetracosenoic acid, NA) is a very
long-chain fatty acid whose name originated from the original dis-
covery in mammalian nerve tissues. The nutrient plays a vital role in
human health, especially for the brain. NA combines with sphingosines
via amide bond to form nervonyl sphingolipids, which are an important
component in the white matter of brains and myelinated nerve fibers.
NA is closely associated with the development and maintenance of the
brain and the biosynthesis and improvement of nerve cells. As a natural
component of maternal milk, NA can also promote the growth of infants
by assisting their nervous system development.
NA is found in the seed oils of some wild plants, including Lunaria
annua (honesty), Acer truncatum (purpleblow maple), Tropaeolum spe-
ciosum (flame flower), Borago officinalis (borage), and Cannabis sativa
(hemp) (Tang et al., 2013). However, the current diseconomy of NA
extracted from plants must be overcome, and its application requires
wide exploitation. The NA production by microorganisms, which may
be an excellent option for the mass production of NA, has attracted
increasing interest (Umemoto et al., 2014).
An increasing number of studies focused on the biological functions
of NA. Various studies have established that supplementation with NA
is effective in the treatment of neurological diseases, such as demyeli-
nating disorders (Sargent, Coupland, & Wilson, 1994). One way of NA
production in the human body is by the conversion from other fatty
acids through a series of biochemical reactions; another way is direct
ingestion, by which NA is readily available to the body. NA is crucial in
pharmacological and nutraceutical applications because of its excellent
biofunctions.
Over the past decades, the explorations of NA have already identi-
fied its importance to human health, considerable developmental po-
tential, and brilliant application prospect. The available information on
the source, production, and functions of NA is summarized in this re-
view.
2. Sources
NA is synthesized from the carbon chain elongation of oleic acid
(C18:1 ω-9), in which two C units donated by malonyl-CoA are cycli-
cally added to the acyl chain. The cycle occurs at the endoplasmic re-
ticulum membrane, where four steps are included (Fig. 1). 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 gen-
eration 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

⁎
Corresponding authors.
E-mail addresses: xiuzhuyu@nwafu.edu.cn (X. Yu), jinminggao@nwafu.edu.cn (J.-M. Gao).

https://doi.org/10.1016/j.foodchem.2019.125286
Received 10 April 2019; Received in revised form 26 July 2019; Accepted 28 July 2019
Available online 29 July 2019
0308-8146/ © 2019 Elsevier Ltd. All rights reserved.
Q. Li, et al. Food Chemistry 301 (2019) 125286

Fig. 1. NA biosynthesis pathway (Huai et al., 2015).

involved in this process function in all tissues and possess broad sub- value for utilization and exploitation as NA-extracting raw materials.
strate specificity. Thus, KCS is the rate-limiting enzyme of the NA The amounts of NA are affected by growing conditions and planting
biosynthesis pathway (Yang et al., 2018). pattern; for example, nitrogen applications in oilseed crops can improve
oil yield and NA content (Zheljazkov, Vick, Ebelhar, Buehring, &
Astatkie, 2012).
2.1. Oil plants For NA production with oil seeds, the critical and tricky problem is
diseconomy because seeds may fall to the ground during harvesting and
NA has been identified in some oil plants, thereby providing a good are prone to breakage. L. annua and A. truncatum are considered niche
source of NA (Table 1). L. annua, which is generally grown for its or- species in practice. The rest of crops still need further research and
namental value in many countries, is a biennial cruciferous oil seed development, and a genetically modified technique may be an alter-
crop. The oil content of its seeds is in the range of 30%–35%, re- native method.
markably consisting of 23% NA, and the nonedible fatty oil is explored
as a renewable source for fuels and lubricants (Dodos, Karonis,
2.2. Oleaginous microalgae
Zannikos, & Lois, 2015). NA concentrations of the total fatty acids ex-
hibit an important effect on the properties and quality of biodiesel.
Oleaginous microalgae are feasible for NA development. The finding
T. speciosum, a rare plant growing in Chile, is one of the richest
that NA makes up to 3.8% of the total fatty acid content in microalgae
sources of NA (43% of the total fatty acid content). NA accounts for
(Mychonastes afer HSO-3-1) expands the available sources of NA (Yuan
8.6% of X. caffra oil, in which lignoceric acid is associated with the
et al., 2011). The culture conditions of NA-producing microalgal strain
etiology of adrenoleukodystrophy (ALD) and multiple sclerosis (MS).
must be optimized to increase the contents of lipid and NA. The treat-
Thus, it will be bothersome for its exploitation because lignoceric acid
ment of bioactive additives (such as 1-naphthylacetic acid and tea
would need to be separated from NA (Chivandi, Davidson, & Erlwanger,
polyphenol) at different growth stages can prompt M. afer cell growth,
2008). NA is the major fatty acid in Malania oleifera (55.7%–67.0%),
thereby increasing NA accumulation (Xu et al., 2018). The expression of
which is an endangered woody oil plant that grows naturally in the
the full length of the KCS gene from microalgae M. afer HSO-3-1 can be
west of Guangxi and southeast of Yunnan Province in China.
used to accumulate NA, especially under environmental stress condi-
Another noteworthy plant is A. truncatum, which is a woody crop
tion, and a high fatty acid ratio of C24:1/C22:1 is compared with some
native to northern China, Japan, and Korea, and is also distributed in
plants (Fan, Yuan, Jin, Hu, & Li, 2018).
North America and Europe. The seed oil may be a potential source of
Microalgae possess the potential for large-scale cultivation for their
NA. As confirmed among the 138 accessions of A. truncatum in China,
fast growth rate and high oil content. The industrial production of NA
NA content is in the range of 3.9%–7.8%, which can be ascribed to
with microalgae and other microorganisms is considered viable.
environmental variations (Qiao, Xue, & Feng, 2018). The NA of seed
Umemoto et al. (2014) found a high-NA-producing filamentous fungus
kernel oil of X. sorbifolia is present in an average relative content of
of the Mortierella that is capable of NA accumulation at a rate of 6.9%;
2.2% in China.
new microalgae species producing high NA should be further explored.
Plants containing both high oil levels and abundant NA possess high

Table 1 3. Production
Main plant seeds rich in NA.
3.1. Separation and purification
Sources Oil content (%) NA content of total fatty acid (%)

Malania oleifera seed 59.1–61.5 55.7–67.0 NA can be isolated and purified by crystallization from mixed fatty
Lunaria annua seed 30.0–35.0 21.8–24.2 acids on the basis of the different solubility and temperature depen-
Ximenia caffra seed 40.1–55.1 5.9–11.4 dence of the mixture in a solvent. The performance is mainly affected
Acer truncatum seed 45.0–48.0 3.9–7.8
by solvent types. The recovery and purity of NA product are also sub-
Tropaeolum speciosum seed 12.3–15.7 40.6–45.4
Xanthoceras sorbifolia seed 63.3–69.5 2.0–2.4 jected to other factors, such as material-to-solvent ratio, cooling crys-
tallization temperature, and cooling crystallization speed.

2
Q. Li, et al.
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 NA separation,
and acidification is subsequently applied (Lin, Wang, & Wu, 2008). The
merits of economy, high yield, and good removal of low carbonated
fatty acids elevate the feasibility of metal salt precipitation.
Molecular distillation, which is also known as short-path distilla-
tion, is a special high-vacuum liquid–liquid separation technique ac-
cording to the average distance of molecular freedom motion. NA ex-
traction could be achieved in the separation process. The NA proportion
in fatty acids of A. truncatum L. can be increased to 39% through wiped
film molecular distillation (Zhang & Hou, 2010). NA purification by
molecular distillation is easy to operate and has high separation effi-
ciency and satisfactory resistance to product deterioration and decom-
position.
The NA content of A. truncatum can be improved to 18% by pur-
ification with high-speed countercurrent chromatography (HPCC). The
best solvent system for HPCC is a ternary solvent system consisting of n-
hexane, ethanol, and water (Zhao, Zhu, & Wang, 2016). The results
indicate that a weakly polar solvent system is suitable because NA is a
weakly polar molecule.
Urea adduction fractionation (UAF) is a simple method in separ-
ating 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 (Xu, Wang, & Liang, 2017). Low processing temperature
preserves the molecular structure, physicochemical properties, and
physiological activity of NA 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 purifica-
tion of NA, whereas the characteristics of various extraction methods
result in the differences in production yield, quality, and purity of NA.
Furthermore, the extraction processing method used in oil production is
essential for NA preservation. Ultrasonic circulating extraction is ap-
plied to samara oil production from Acer saccharum, and the yield of
samara oil (11.72 ± 0.38%) and content of NA (5.28 ± 0.18%) are
achieved (Chen, Zhang, Fei, Gu, & Yang, 2016). Supercritical CO2 fluid
extraction performs well through the optimization of M. oleifera oil
extraction, and free NA content can reach 5.4% (Luo, Chen, Wang, &
Ge, 2015).
3.2. Application of transgenic technique and microbial production
NA is not contained in the main vegetable oils (e.g., soybean, ra-
peseed, sunflower), and the low proportion in some of other natural
oilseeds limits its production. Heterologous KCS has been expressed in
transgenic oilseeds, e.g., KCS gene isolated from Lunaria, to improve NA
production. Efficient Cardamine graeca KCS transgenic Brassica oilseeds
have been studied to improve NA productivity (Taylor et al., 2010). The
optimal NA content in Camelina sativa oil increases to 6%–12% in KCS
(the rate-limiting enzyme)-expressing lines, whereas the increase is not
significant with respect to combinatorial effects with other fatty acid
elongase enzymes (Huai, Zhang, Zhang, Cahoon, & Zhou, 2015). In
terms of industrial scale with plants, the cultivation of climate, geo-
graphical location, and hydrology are all important factors to be con-
sidered.
The application of metabolic engineering technique in oleaginous
yeasts for NA production is feasible. The de novo synthesis of NA in
Rhodosporidium toruloides (oleaginous yeast) is confirmed through the
heterologous expression of KCS from different plants. The codon opti-
mization and synthesis of the coding sequences for KCS genes are first
performed to generate plasmids. Then, the host cells are transformed
and are cultivated in proper growth conditions. Microbial oil is
3
Food Chemistry 301 (2019) 125286
obtained by performing acidic hydrolysis of dry yeast biomass, filtra-
tion for cell debris removal, Soxhlet extraction with hexane, and eva-
poration. However, NA is undetected in R. toruloides by the expression
of L. annua KCS, which is different from the results of in vitro tests
(Fillet et al., 2017). KCS from different sources exhibits a different ef-
ficiency in NA production, indicating that the substrate specificity of
elongase must be investigated. Increasing gene dosage and coexpression
of elongases are the potential approaches in improving NA production
(Fillet et al., 2017; Huai et al., 2015).
4. Functions
NA, a monounsaturated omega-9 fatty acid important in the bio-
synthesis of myelin in the brain, can be an indicator of brain matura-
tion. Brain sphingomyelin level is consistent with NA level in red cells
(Martinez, 1992); it has significant biological functions, such as pro-
moting brain development, improving memory, and delaying brain
aging. Obese adolescents have higher NA levels in serum phospholipid
fatty acids than lean subjects (Karlsson et al., 2006). Thus, the theo-
retical basis of NA marketed as enriched energy supplements with
neuro-protective effect needs to be explored.
4.1. Benefits to brain tissue
Dietary NA or EA elevates the NA proportion of sphingolipids in
humans (Barre & Holub, 1992). Dietary NA as a free fatty acid can cross
the mammary epithelium and incorporate milk sphingomyelin. Subse-
quently, milk NA is transferred across the intestinal epithelium and is
accumulated in tissues of suckling rats (Bettger, Dimichelle-Ranalli,
Dillingham, & Blackadar, 2003). Dietary NA supplied by T. speciosum oil
extract (0.125 wt% in diet) improves the sphingomyelin NA 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 (Bettger, McCorquodale, & Blackadar, 2001). Therefore, NA, in-
cluding those in the form of triglycerides or sphingosine, may easily
cross the intestinal tract and mammary epithelial barrier and accumu-
late in heart and liver tissues.
However, NA present in triacylglycerol or its free state does not
readily penetrate the blood brain and placental barriers. Dietary oil
(Lunaria oil, 6.8% of NA in the test diet), which is rich in NA and erucic
acids (EA, C22:1), causes normal NA 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 NA in the blood is unavailable to the brain because
it can no longer cross the blood–brain barrier (Cook, Barnett, Coupland,
& Sargent, 1998).
NA concentration is lower in preterm placentae than in placental
tissue of the term deliveries. The decrease may affect the baby head
circumference, which may be connected with brain development
(Dhobale, Wadhwani, Mehendale, Pisal, & Joshi, 2011). NA levels are
correlated with early development of premature infants. The brain
maturity of premature infants is associated with the NA levels in the
sphingomyelin of the brain. In addition, the high NA in premature
breast milk serves as the compensation for early infancy for premature
infants. For infant formulas with enhanced NA (0.1% by mass), animal
tests and human food safety evaluation have shown that the brain de-
velopment and intelligence of infants can be promoted.
Cognitive function impairment, induced by 1-bromopropane in rats,
can be protected by NA intake. The possible cause is the activity im-
provement of γ-glutamate cysteine ligase in the cerebral cortex (Yuan
et al., 2013). Oral NA supplementation can enhance learning memory
in animal (normal mice and mice with experimental memory impair-
ment) models as proved by water-maze swim and platform step-down
technologies (Li, Tan, Bi, Yin, & Zhu, 2004). Consequently, NA pos-
sesses a possible potential in enhancing human memory and cognitive
Q. Li, et al.
function. Systematic and reliable references on the effect of NA in the
general population are still lacking.
4.2. Alzheimer’s disease, psychosis, and depressive disorder
Serum fatty acid composition and erythrocyte membrane phos-
pholipid can be an accessible indicator of fatty acids in the nervous
system, neuronal membranes, and brain phospholipids (Assies,
Lieverse, Vreken, Wanders, & Linszen, 2001; Song et al., 2018). Ac-
cordingly, an investigation and analysis focused on the cognitive im-
pairment 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 NA levels and increases with de-
creasing eicosenoic acid levels (Song et al., 2018). However, some
studies reported conflicting findings. Abnormalities in brain sphingo-
lipid metabolism have an implication on age-related neurodegenera-
tion. Elevated stearoyl-CoA desaturase (SCD), along with NA levels, is
associated with AD (Giuseppe et al., 2011). Prominently increased NA-
containing sphingolipids and SCD in the hippocampus of old male and
female mice indicate the possible contribution of these factors to age-
dependent disorders (Vozella, Basit, Misto, & Piomelli, 2017). The pa-
thogenesis of AD affected by NA remains unclear.
Prodromal symptoms of psychosis have confirmed their close rela-
tion with decreased NA levels in erythrocyte membranes (Amminger
et al., 2012). Furthermore, decreased NA levels are observed in the red
blood cells of patients with psychosis (Assies et al., 2001; Evans et al.,
2003). Conversely, NA levels are also evidently high in psychotic pa-
tients and their unaffected siblings (Medema et al., 2016). The con-
tradiction may be due to different disease groups, periods of onset, drug
use, and living environments.
Johanna et al. (2010) reported that the NA levels in the plasma and
erythrocytes of patients with recurrent depression are significantly
lower than those in normal people. Conflicting results showed that in-
creased plasma NA levels may be a potential biomarker for major de-
pressive disorder assessment (Kageyama et al., 2018). The incon-
sistency may be attributed to the differences in subtypes of major
depressive disorder (recurrent vs. nonrecurrent).
4.3. Demyelinating disease
Demyelinating diseases, such as ALD, MS, and Zellweger syndrome,
are autoimmune diseases characterized by demyelinated white matter
of the central nervous system. Insufficient NA in mice leads to impaired
myelination. The decreased NA levels in sphingolipids are identified by
the post mortem of ALD brain. In addition, diets rich in NA can improve
ALD (Eliton, Brucec, & Kennedyh, 2008). The decrease in NA is asso-
ciated with demyelinating diseases, and exogenous NA can synthesize
sphingolipid ester (such as ganglioside and cerebroside) and sphingo-
myelin. The myelination of nerve fibers is promoted, thereby re-
generating the resected myelin. Consequently, the symptoms are im-
proved, which contributes to the recovery of the impaired nerve fibers.
Early dietary treatment with Lorenzo’s oil (EA:oleic acid = 4 to 1,
precursors for NA synthesis) and docosahexaenoic acid (DHA) can help
neurological development in patients with Zellweger syndrome
(Tanaka, Shimizu, Ohtsuka, Yamashiro, & Oshida, 2007).
4.4. Cardiovascular disease and chronic kidney disease
An investigation on the association of erythrocyte omega-9 mono-
unsaturated fatty acid and all-cause and cardiovascular mortality re-
vealed that NA is an independent predictor of cardiovascular death
(Delgado et al., 2017). NA could act as a predictor of all-cause mortality
of patients with stage 5 chronic kidney disease; in addition, patients are
at a 2.1-fold increased risk of age-adjusted death for every 0.15% in-
crease in NA level of red blood cells (Shearer, Carrero, Heimbürger,
Barany, & Stenvinkel, 2012). Statistical data show that consuming high
4
Food Chemistry 301 (2019) 125286
NA levels has possible unfavorable effects. However, a real cause and
effect has not been accurately shown.
4.5. Acquired immunodeficiency syndrome
A soft-gel capsule, which is specially processed from A. truncatum
oil, enhances immunity by promoting the proliferation and transfor-
mation of spleen lymphocytes, the activity of natural killer cells, the
level of serum hemolysin, and the amount of antibody-producing cells
in mice (Wang et al., 2008). NA exhibits competitive inhibition of
deoxyribonucleic acid polymerase β activities. The inhibitor decreases
the association rate of polymerase β-duplex interaction by almost
twofold, and the dissociation rate increases ninefold (Jun et al., 2009).
5. Conclusions and perspective
Plants and microalgae are main sources of NA for various applica-
tions. Through breeding techniques, edible NA-rich oil crops may in-
crease their seed oil contents and improve their fatty acid composition.
These rare plant species, such as M. oleifera, must be protected. The
difficulty of using these natural plants as sources of NA is mainly re-
flected in diseconomy. Hence, for NA industrial production, algae can
be a potentially renewable source, and new microalgae species that
exhibit increased efficiency must be found. The application of genetic
engineering also contributes to NA yield improvement.
Efficient methods of NA production have considerable importance
on its application, especially when serving as precursors for the phar-
maceutical industry. Multiple crystal purification can improve NA
purity to some extent, whereas the utilization of organic solvents may
damage the environment. The purification effectiveness of metal salt
precipitation is superior to that of crystallization, but the method re-
quires acetone as a solvent. Molecular distillation and HPCC exhibit
better purification, but both require expensive equipment. Importantly,
HPCC produces a low sample throughput. Considering the costs and
security concerns, UAF may be the choice for most producers at present.
Furthermore, highly purified NA can be obtained with the combination
of these methods (e.g., UAF and molecular distillation). Other methods
with the advantages of efficient, economic, nontoxic, and yielding high-
purity NA must be explored and spread.
NA has an extremely close relationship with brain health. Therefore,
a continuously increasing emphasis will be placed on the development
of pharmaceutical and nutraceutical applications for the treatment of
brain diseases and other diseases, such as demyelinating diseases.
Formula feeding may enhance neurodevelopment for infants and pro-
vide a healthy alternative to milk powder for consumers and manu-
facturers. However, contradicting results in terms of the NA levels of
patients with AD, psychosis, depressive disorder, and cardiovascular
disease warrant further investigation, thereby indicating pressing
questions on the related disease and the action mechanism of NA.
NA levels of 0.1% or less in dietary intake can be involved in myelin
membrane formation outside the myelinated nerve fibers in extraneural
tissues. Higher levels of NA in the diet could modulate the metabolism
of lipid and energy by binding to transcription factors and carrying out
gene expression regulation (Van Meer, Voelker, & Feigenson, 2008;
Zheng et al., 2006).
Recent reports suggest that dietary lysophosphatidylcholine (LPC)-
DHA and LPC-EPA are better incorporated in the brain, enriching brain
DHA and EPA (Sugasini, Thomas, Yalagala, Tai, & Subbaiah, 2017).
Notably, a sodium-dependent membrane transporter (Mfsd2a) trans-
ports DHA as LPC form into the brain (Long et al., 2014). Moreover, a
transport method of passing NA through the blood–brain barrier may be
present, particularly for newborns less than 2 weeks. Therefore, the
hypothesis that a specific physiological transport at the blood–brain
barrier may allow NA incorporation and the allowed form of NA needs
to be tested to elucidate the mechanisms underlying NA transport. The
mechanism of dietary and physiological factors for NA levels and
Q. Li, et al.
molecular forms in vitro and in vivo has not been explicitly detailed.
Considerable research on the molecular, cellular, tissue, animal, and
human mechanisms is needed.
Declaration of Competing Interest
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influ-
ence the work reported in this paper.
Acknowledgement
The authors would like to thank the National Natural Science
Foundation of China (NO.: 31671819) for the financial support.
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