Download Unsaturated Fatty Acids, Desaturases, and Human Health

JOURNAL OF MEDICINAL FOOD
J Med Food 17 (2) 2014, 189–197
# Mary Ann Liebert, Inc., and Korean Society of Food Science and Nutrition
DOI: 10.1089/jmf.2013.2917
Unsaturated Fatty Acids, Desaturases, and Human Health
Hyungjae Lee1 and Woo Jung Park 2
2
1
Department of Food Engineering, Dankook University, Cheonan, Korea.
Department of Marine Food Science and Technology, Gangneung-Wonju National University, Gangneung, Korea.
ABSTRACT With the increasing concern for health and nutrition, dietary fat has attracted considerable attention. The
composition of fatty acids in a diet is important since they are associated with major diseases, such as cancers, diabetes, and
cardiovascular disease. The biosynthesis of unsaturated fatty acids (UFA) requires the expression of dietary fat-associated
genes, such as SCD, FADS1, FADS2, and FADS3, which encode a variety of desaturases, to catalyze the addition of a double
bond in a fatty acid chain. Recent studies using new molecular techniques and genomics, as well as clinical trials have shown
that these genes and UFA are closely related to physiological conditions and chronic diseases; it was found that the existence
of alternative transcripts of the desaturase genes and desaturase isoforms might affect human health and lipid metabolism in
different ways. In this review, we provide an overview of UFA and desaturases associated with human health and nutrition.
Moreover, recent findings of UFA, desaturases, and their associated genes in human systems are discussed. Consequently, this
review may help elucidate the complicated physiology of UFA in human health and diseases.
KEY WORDS: dietary fat-associated genes fatty acid desaturase (FADS) health and development
monounsaturated fatty acids polyunsaturated fatty acids stearoyl-CoA desaturase (SCD)
lipids, including long chain polyunsaturated fatty acids
(LCPUFA). The isoforms and physiological functions of
SCD and FADS have been investigated for more than a
decade with the development of molecular techniques and
transgenic mice.6 Recently, the alternative transcripts of
FADS genes7 and a novel function of FADS1 transcriptional
isoform have been reported to regulate PUFA synthesis.8
Human genome data have also facilitated analyses of the
association of FADS genes with human health, suggesting
PUFA and FADS genes are essential for human health and
physiological development.4
In this review, we summarize the current knowledge of
UFA, such as MUFA and PUFA, closely related to human
health and diseases. Moreover, the well-known functions
and biosynthesis of SCD and FADS are described, and recent new findings on the implications of SCD and FADS in
diseases and physiological conditions using state-of-the-art
techniques are discussed.
INTRODUCTION
D
ietary fat composition is highly essential for the
maintenance of human health, the prevention of lipidassociated diseases, and development.1 Especially, unsaturated fatty acids (UFA) are considered nutritionally important, and desaturases are the main enzymes to synthesize
UFA in biological systems.2 Monounsaturated fatty acids
(MUFA) containing only one double bond in their structure
are mostly synthesized by stearoyl-CoA desaturase (SCD),
which is known to be associated with obesity, insulin resistance, and skin diseases.3 Polyunsaturated fatty acids
(PUFA), including more than two double bonds are generated by several fatty acid desaturases (FADS); the genes
encoding FADS were reported to be related to many diseases, such as cardiovascular disease, diabetes, and allergy,4
and physiologically important for brain development and
cognition.5
Many UFA studies have been performed to understand
the biological properties of the fatty acids and their beneficial effects on human health. Recent advances in molecular
biology, including genetic and genomic techniques, have
enabled scientists to better understand desaturases and their
association with health and diseases, as well as diverse
BIOSYNTHESIS OF UFA
MUFA, such as palmitoleic acid (16:1n-7) and oleic acid
(18:1n-9) are synthesized by SCD (Fig. 1A).3 Alternatively,
an isoform of palmitoleic acid (16:1n-10) can be generated
by delta-6 desaturase (FADS2) in biological systems9 as
shown in Figure 1A. Omega-9 fatty acids are assumed to be
synthesized from these MUFA by delta-5 and delta-6 desaturation and/or several elongation pathways, such as biosynthesis of omega-3 and omega-6 fatty acids.6
Manuscript received 17 April 2013. Revision accepted 4 September 2013.
Address correspondence to: Woo Jung Park, PhD, Department of Marine Food Science
and Technology, Gangneung-Wonju National University, Gangwon 210-702, Gangneung,
Korea, E-mail: [email protected]
189
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LEE AND PARK
FIG. 1. Schematic representation of unsaturated fatty acids (UFA) biosynthesis in mammals. (A) Biosynthetic pathway of monounsaturated
fatty acids (MUFA). MUFA is mostly catalyzed by stearoyl-CoA desaturase (SCD, delta-9 desaturase). SCD helps the introduction of a double
bond at the ninth carbon-carbon bond from the carboxylic end in stearic acid (18:0) to generate oleic acid (18:1n-9). In addition, palmitoleic acid
(16:1n-7) can be synthesized by SCD and an isoform of the palmitoleic acid (16:1n-10) can be generated by delta-6 desaturase (FADS2) in a
biological system. (B) Biosynthetic pathway of polyunsaturated fatty acids (PUFA). Mammals, including humans cannot produce linoleic acid
(LA, 18:2n-6) and a-linolenic acid (ALA, 18:3n-3), dietary essential fatty acids, which must be consumed in the diet. They can synthesize other
PUFA by several desaturation and elongations. Delta-6 desatuarse (FADS2) and delta-5 desaturase (FADS1) catalyze the desaturation of the sixth
and the fifth carbon from the carboxylic end in a fatty acid chain, respectively. Delta-4 desaturase catalyzes introduction of a double bond at the
fourth carbon from the carboxylic end in a fatty acid chain. This enzyme was demonstrated only in marine vertebrate and lower eukaryotes. Up till
now, docosahexaenoic acid (DHA) has been recognized to be synthesized by FADS2 and peroxisomal b-oxidation in mammals.
In contrast, the essential fatty acids, linoleic acid (LA,
18:2n-6) and a-linolenic acid (ALA, 18:3n-3) must be
consumed in the diet because these fatty acids cannot be
synthesized by mammals, including humans. These two
fatty acids, LA and ALA can be changed into a variety of
omega-6 and omega-3 fatty acids by a series of desaturases
and elongases, respectively (Fig. 1B);6 the conversion of LA
to c-linolenic acid (GLA, 18:3n-6) and ALA to 18:4n-3 are
catalyzed by delta-6 desaturase, FADS2.10 The production
of dihomo-c-linolenic acid (DGLA, 20:3n-6) to arachidonic
acid (ARA, 20:4n-6) and 20:4n-3 to eicosapentaenoic acid
(EPA, 20:5n-3) are synthesized by delta-5 desauturase,
FADS1.11 Twenty-carbon PUFA are known as eicosanoid
precursors, among which ARA is a well-known proinflammatory eicosanoid precursor. In contrast, both EPA and
DGLA are anti-inflammatory eicosanoid precursors.12,13
However, delta-8 desaturation is an alternative pathway for the
production of PUFA in which FADS2 also acts as a delta-8
desaturase, and was shown to synthesize DGLA and 20:4n-3
from 20:2n-6 to 20:3n-3, respectively. This suggests that this
pathway may be critical under conditions in which a high rate
eicosanoid synthesis is required.14 The two-carbon elongations
of GLA to DGLA and 18:4n-3 to 20:4n-3 are catalyzed by an
elongase, ELOVL5.6 It is widely recognized that the substrates
for the biosynthesis of docosahexaenoic acid (DHA, 22:6n-3)
and docosapentaenoic acid (DPA, n-6, 22:5n-6) are 24:6n-3
and 24:5n-6 for the peroxisomal oxidation, respectively, and
that two-carbon elongation and the subsequent delta-6 desa-
turation of ARA and EPA occurs for the production of 24:5n-6
and 24:6n-3, respectively (Fig. 1B).15
UFA AND DESATURATION
Desaturases generate a double bond in a fatty acid chain to
produce a variety of UFA. According to the position of double
bond, the enzymes are classified into different groups of desaturases: delta-9, delta-6, delta-5, or delta-4 desaturases.2
Delta-9 desaturase catalyzes desaturation of the ninth
carbon-carbon bond from the carboxylic end in a fatty acid
chain. This enzyme is also called SCD, which catalyzes
mainly the desaturation of saturated fatty acids (SFA), such as
palmitic acid (16:0) and stearic acid (18:0) (Fig. 1A).2,6
Transgenic mouse studies have revealed a variety of physiological roles and regulatory pathways associated with those
Scd genes and proteins.16,17 Delta-9-desaturase has been reported to be associated with obesity, atherosclerosis, and even
skin diseases.3,18 Scd1 deficient mice showed several distinctive physiological changes in lipid biosynthesis and insulin
sensitivity in liver, muscle, and adipose tissues.3,16 These
variations that might be caused by transcriptional or posttranscriptional effects would be associated with obesity,
insulin resistance, diabetes, and hyperlipidemia causing metabolic syndrome.3 Scd2 deficient mice displayed changes in
skin and liver development related to lipid synthesis. Unlike
its roles in Scd1 in adult mice, Scd2 was responsible for the
synthesis of MUFA in neonates.17 However, there has been no
UFA, DESATURASES, AND HUMAN HEALTH
report investigating the other two genes, Scd3 and Scd4 as yet.
Scd3 does not have a catalytic activity on stearic acid but does
for palmitoic acid, implying that Scd3 can be considered as a
palmitoyl-CoA desaturase unlike other SCD isomers.19
Delta-6 desaturase is so named because it catalyzes the
formation of a double bond at the sixth carbon-carbon
bond from the carboxylic end in a fatty acid chain. Delta-6deasturase, a rate-limiting desaturase for the production of
PUFA, is known to serve multiple functions, including
delta-6 desaturation activities on LA and ALA (Fig. 1B).2,10
In addition to the delta-6 desaturase activity, the enzyme
exhibited another delta-6 desaturation activity to produce
16:1n-10 fatty acid from palmitic acid,9 which is also important for the skin of animals, including humans.20 Delta-6desaturase was also reported to participate in peroxisomal
b-oxidation to produce DHA, as shown in Figure 1B.21
Recently, Park et al. showed that delta-6 desaturase encoded
by FADS2 also had catalytic activities on 20:2n-6 and
20:3n-3 as a delta-8 desaturase;14 Fads2 deficient mice exhibited physiological malfunctions, accompanied by the
consequent LCPUFA deficiency, which led to the abnormal
conditions of reproduction, skin and intestine without affecting viability.22,23 The knockout mice also displayed
tissue-dependent changes in LCPUFA contents. However,
ARA supplementation in a diet reversed the dermatitis and
intestinal ulcers in the knockout mice; however, the diet
could not change DPAn-6 levels in the brain.
Delta-5 desaturase is an enzyme that catalyzes the generation of a double bond at the fifth carbon-carbon bond
from the carboxylic end in a fatty acid chain. This desaturase
acts on DGLA and 20:4n-3 to produce ARA and EPA, respectively.11 Moreover, the enzyme was reported to catalyze
the production of 20-carbon PUFA derived eicosanoids.13,24
Very recently, Fads1 deficient mice generated by Fan et al.25
were not able to produce ARA and ARA-derived eicosanoids related to inflammation, vasoconstriction, and allergic
diseases in humans, as well as development of many diseases, such as cancers with serious problems in intestinal
crypt proliferation, immune cell homeostasis, and sensitivity
to acute inflammatory challenge.24 In addition, the mice
lacking ARA were not able to survive more than 12 weeks,
but dietary ARA helped extend their life span.
Delta-4 desaturase catalyzes the formation of a double
bond at the fourth carbon-carbon from the carboxylic
acid end in a fatty acid chain. This enzyme is important for
the biosynthesis of DHA, which is an important nutrient
for the early development and diverse physiological
conditions. Up till now, there is no report that delta-4
desaturase is synthesized in mammals, but lower eukaryotes have been reported to generate this enzyme.26,27
Recently Li et al. reported that marine vertebrates encoded delta-4 desaturase genes expressed in their systems
(Fig. 1B).28
SCD and isoforms
Humans contain two SCD isoforms, SCD1 and SCD5;29,30
however, mice have four different isoforms, Scd1, Scd2, Scd3,
191
and Scd4, highly homologous to the human SCDs.19 SCD1, a
human SCD gene encoding 359 amino acids (aa) is located at
human chromosome 10q24.31. SCD5, the other SCD gene
highly expressed in the brain and pancreas, is located at
chromosome 4q21.22. SCD5 is composed of four exons and
three introns, and its expressed protein contains 256 aa. SCD
proteins have three conserved histidine boxes in the structure,
which are assumed to act as catalytic domain chelating an
iron.6 SCD is also known to collaborate with NADH, cytochrome b5 as an electron donor, flavonprotein reductase, and
molecular oxygen in the endoplasmic reticulum.31 Recently,
Sinner et al. reported that SCD5 expression might be associated with the growth and differentiation of neuronal cells.30
Animal studies have shown that SCD is tissue-dependently
expressed;6 Scd1 was differently expressed in adipose tissue
and liver in animals according to diet.32 The expression level
of Scd2 was found to be high in brain and neuronal tissues.33
In contrast, Scd3 was expressed in sebocytes and harderian
and preputial glands, but Scd4 is uniquely expressed in
heart.34
FADS and alternative transcripts
In human chromosome 11, there are three FADS genes for
the biosynthesis of PUFA: FADS1, FADS2, and FADS3.
They are localized at 11q12.2–11q13.1, consisting of 12
exons and 11 introns. FADS1 and FADS2 are composed of
444 aa unlike putative FADS3 containing 445 aa. However,
all the three enzymes have a common N-terminal cytochrome b5 domain and three histidine boxes in contrast to
SCD having no cytochrome b5 domain. Recently, an alternative transcript of FADS2 (FADS2 AT1) and seven alternative transcripts of FADS3 (FADS3 AT1–AT7) were found
to be expressed in various baboon tissues and human neuroblastoma cells, SK-N-SH.35,36 Putative coding region of
FADS2AT1 contains only three histidine boxes without
cytochrome b5 domain. This structure suggested that the
role of the alternative transcript would be associated with
the desaturation of nonmethylene interrupted PUFA.35 The
seven alternative transcripts of FADS3 exhibited a variety
of structural and expression characteristics. Among the
transcripts, FADS3 AT1 and AT3 include a conserved Nterminal cytochrome and three histidine domains. FADS3
AT5 uniquely retains intron 5. In addition to FADS2, FADS3
transcripts were expressed in a tissue-specific manner and the
expression pattern was changed depending on the neuronal
cell differentiation.7,35,36 Moreover, the protein isoforms of
FADS3 expressed in a tissue-dependent fashion were identified in both human cells and rodent tissues.37 However, no
evident function of FADS3 has been reported since the first
report in 200038 even though FADS3 has been reported to
be an important gene for hyperlipidemia39 and implantation
sites.40 Recently, Park et al. found new alternative transcriptional isoforms of FADS1 by using 50 - and 30 -RACE
analysis, and they identified the function of a new isoform
that potentiates the delta-6 desaturations of FADS2.8 This
finding was the first report that one gene’s function can be
regulated by another gene’s splice variant.
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IMPORTANCE OF DIETARY UFA
TO HUMAN HEALTH
Dietary fat, including fat soluble vitamins and essential
fatty acids is indispensable for human health and nutrition as
a main energy source. Fat in a diet can play a key role for the
prevention of diseases depending on its compositional
changes.1 Many diseases, including cardiovascular disease
and cancers are associated with metabolic changes in SFA
and their metabolites.41
Effect of UFA on human health and development
It was reported that changes in SFA and triglyceride
levels may considerably affect SCD activity of lipotoxic
mechanisms in nonalchoholic fatty liver disease (NAFLD)
patients.42 In particular, LCPUFA have been considered
major nutrients in the control of many physiological conditions for human health and development; the biosynthesis
and/or bioavailability of LCPUFA were found to be linked
to the occurrence of NAFLD,43 autoimmune diseases,24 and
other chronic diseases, including cancers and diabetes. In
particular, eicosanoids and/or docosanoids derived from
LCPUFA, such as prostaglandins, prostacyclins, and leukotrienes are crucial cellular signal molecules that are associated with inflammatory and immune regulation.44
Two omega-3 LCPUFA, EPA, and DHA were reported to
positively affect immune responses and immune-related
diseases, such as arthritis and asthma.13 Recently, the supplementation of these LCPUFA was also found to make
beneficial effects on the treatment of the colon and breast
cancer patients.45,46 Furthermore, LCPUFA are reported to
be essential for brain development as major components of
the human brain.5 These fatty acids are considered to be vital
components in human breast milk and baby formula.47–49
The level of the fatty acids rapidly increases up to 24 months
after the birth in the human brain;50 DHA, the most abundant fatty acid in the brain, is known as a key factor for
cognition and brain health, as well as the prevention of
neurodegenerative diseases, such as Alzheimer’s disease
and cognitive decline.51 Aside from the important roles for
brain development and health, DHA is one of the most
important structural constituents for visual function in the
eyes; DHA in the retina may lead to the alteration of permeability, fluidity, and lipid phase characteristics, resulting
in the change of photoreceptor membrane function.52
Importance of omega-6 to omega-3 ratio in a diet
Even though UFA show beneficial effects on human
health, the high ratio of omega-6 to omega-3 fatty acids is
considered a major contributor to the pathogenesis of many
diseases, such as cardiovascular disease, diabetes, and cancers.1,53 In the present Western diet, the ratio has been much
higher than that in the ancient, Mediterranean, or Japanese
diet; the ratio of the current Western diet is greater than
15:1.53 Consequently, as the Western diet consumption has
increased, there has been much concern over many diseases
related to the consumption of high-fat diet and metabolic
syndromes, obesity, and diabetes.24 However, dietary
change in omega-6/omega-3 ratio has been reported to be
able to prevent and treat the diseases.24,54 In contrast, the
beneficial effects of the Japanese and Mediterranean diet on
human health is attributable to the ratio of omega-6/omega3 lower than 4:1, as well as high amounts of fish or diverse
vegetable oils in the diets.55,56 The consumption of a Mediterranean diet resulted in *70% decrease in mortality rate
of cardiovascular disease.57 Furthermore, reduced omega-6/
omega-3 ratio in a diet supplemented with fish oil decreased
rectal cell proliferation of patients with colon cancer.58 The
reduction of omega-6/omega-3 ratio also may decrease the
risk of breast cancer,59 relieve rheumatoid arthritis,60 and
have beneficial effects on asthma.54
Desaturases and human health
Due to increasing Western diet consumption containing
high SFA and omega-6/omega-3 ratios, many diseases, such
as cardiovascular disease, diabetes, and cancers have come
to be major diseases in the United States and other countries.1 As a consequence, the rising concern over health and
nutritional effects of diet on human health has led to new
emphasis on nutritional genetics and genomics by studying
the relationship between nutrients or food components and
transcriptional change of relevant genes in human beings.
Table 1 summarizes major physiological conditions, including chronic diseases associated with desaturase genes
through recent genetic and genomic studies. The consumption of dietary fat with different fatty acid compositions and the diseases or physiological change caused by
those nutrients and related genes has been investigated by
referring a wide range of relevant knowledge and by using
newly developed techniques. Moreover, UFA have been
studied for their preventive effects on these diseases and
the clinical and population implications have been explored.4,61–63
Table 1. Desaturase Genes, Substrates for the Gene,
and Their Associated Diseases and Physiological Conditions
Genes
SCD
Substrates for catalytic
activity (fatty acid)
Associated diseases and
physiological conditions
16:0, 18:0
Obesity, insulin resistance,
atherosclerosis, and
hyperlipidemia;3 skin disease;18
neuronal differentiation30
FADS1
20:2n-6, 20:3n-3,
Cholesterol level and coronary
20:3n-6, 20:4n-6
artery disease;65 insulin
resistance;74 breast cancer82
FADS2 16:0, 18:2n-6, 18:3n-3, Conditional change of skin,
reproductive systems, and
20:2n-6, 20:3n-3,
intestine;22,23 infant IQ;68
24:4n-6, 24:5n-3
ADHD;71 breast cancer;82
statin sensitivity83
FADS3
Unknown
Hyperlipidemia;39 implantation
in uterus;40 neuronal
differentiation69
ADHD, attention-deficit/hyperactivity disorder.
UFA, DESATURASES, AND HUMAN HEALTH
Effect of genetic variation in desaturase genes
FADS haplotypes and coronary artery disease inflammation were investigated in people consuming a Westernized diet that contained excessive meat and low amounts of
vegetables. The population consuming the diet showed a
tendency for fatty acid desaturations that were highly associated with proinflmmatory conditions, resulting in the
development of atheroscelerotic vascular damage.64 The
genomic association of plasma omega-3 and omega-6 fatty
acids was analyzed in the InCHIANTI study, suggesting that
the significantly associated locus was rs174537 near FADS1
for ARA.65 The locus was also related to eicosadienoic acid
(EDA, 20:2) and EPA, where minor alleles (TT) were involved in lower levels of longer fatty acids (EDA, ARA,
EPA) and higher levels of LA and ALA. The major allele (GG) in rs174537 near FADS1 induced lower LDLcholesterol levels, but minor allele (TT) also led to lower
LDL-cholesterol levels, contrary to the expectations, suggesting that other mechanism(s) that moderate lipoprotein
homeostasis may exist, and that a transcription factor is
involved because proliferator-activated receptor a (PPARa)
activated the elevation of HDL-cholesterol levels and the
decreases in triglyceride.65 Sergeant et al. also provided
evidence that FADS gene variants in African American and
European American were associated with the levels of serum PUFA and diabetes.66 Moreover, they found that
rs174537 is an important region among people with different levels of PUFA, in which minor allele (TT) showed
lower ARA and higher DGLA major allele (GG) exhibited
higher ARA and lower DGLA. Additionally, Plaisier et al.
showed that the only expression of FADS3 in FADS gene
clusters was associated with the risk of Mexican Familial
Combined Hyperlipidemia.39
Implication of desaturases in human development
LCPUFA, especially DHA, are important for early stage
of brain development since DHA levels sharply increase up
to 24 months.47,50 Many clinical and animal studies have
shown that dietary LCPUFA, including DHA, affects brain
and neuronal systems.47,67 Caspi et al. showed how the relationship between FADS gene and breastfeeding affects the
IQ;68 children’s IQ scores were modulated depending on
rs174575 genotypes in FADS2 and breastfeeding, implying
that genetic difference may act differently on breastfed and
nonbreastfed children probably due to the competition
among desaturases.68
In addition, FADS1 and FADS2 gene clusters affected the
fatty acid composition in pregnant and lactating women,49
indicating that the gene clusters might be intimately related
to brain growth and development in the fetus and neonate.
Furthermore, Tondreau et al. found that FADS3 expression
was associated with neurogenic differentiation from human
bone marrow mesenchymal stromal cells,69 implying that
FADS3 may play an important role in neuronal development. In addition to fetal development, FADS3 might
be important for embryo implantation in uterus, reported by
Ma et al.40 using Serial Analysis of Gene Expression.
193
Aging, a major cause of chronic diseases, is also shown to
be related to adipose fatty acid contents containing SFA and
UFA, such as LCPUFA. The composition of specific fatty
acids changes according to age, implying that functional
loss of several desaturases may occur among the early
middle-aged women, consequently causing the beginning of
diverse diseases accompanied by aging.70
Implication of desaturases in attention-deficit/hyperactivity
disorder
The association of attention-deficit/hyperactivity disorder
(ADHD) with FADS genes has also been investigated.71 In
this study, genetic polymorphisms in FADS genes influenced the incidence of ADHD and the level of cognition. A
significant association of rs498793 in FADS2 with ADHD
suggested that dietary omega-3 fatty acid might be associated with functional problems in the dopamine pathway in
ADHD patients, and the relevant FADS enzymes would
play a key role in the development of ADHD.71
Implication of desaturases in diabetes and insulin
resistance
Kroger et al. examined the relationship among fatty acids
in erythrocyte membranes, desaturases, and dietary consumption of fatty acids for type 2 diabetes;72 it was found
that palmitoleic acid (16:1n-7) and GLA were implicated in
diabetes in multivariable adjusted models, indicating that
SCD and delta-6 desaturase were associated with the diseases even though no significant association of delta-5 desaturase with the disease was elucidated. Warensjo et al.
also showed that SCD was associated with body fat and
insulin sensitivity,63 although the first genetic association
study on SCD did not find any significant connection between SCD genetic variants and type 2 diabetes.73 However,
Elbein et al. reported that FADS1 was associated with the
insulin-resistance74 and recently FADS2 was shown to be
related to insulin-resistance, as well as serum phospholipid
PUFA in healthy Korean men.75 Furthermore, FADS gene
variants in African Americans and European Americans
were investigated for their association with serum PUFA
levels and diabetes.66
Implication of desaturases in cancers
According to cytogenetic and fine mapping studies, the
HSA 11q13 locus containing FADS genes was found to be
a critical location as a major hot spot for cancer development76–78 and microcell-mediated chromosome transfer
suppressed tumorigenecity of breast cancer cells with the
HSA 11q13 locus,79 suggesting that this region may contain a tumor suppressor gene. Diverse cancer cells, including MCF-7 breast cancer cells have been known to lose
delta-6 desaturation (FADS2).80,81 Park et al. elucidated
the functional regulation in FADS2 deficiency between
FADS1 and FADS2,82 in which FADS1 compensates for
the function of FADS2 on 20-carbon fatty acids, implying
that FADS1 was regulated in concordance with FADS2 in
breast cancer cells.
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Interactive regulation of desaturases in lipid physiology
As the interregulation of FADS genes in cancers is mentioned above, it has been found that FADS1 are inter-regulated
with FADS2 in addition to the independent functions of
individual FADS for the synthesis of PUFA associated with
human physiological conditions. Reardon et al. investigated the regulation of FADS genes in lymphoblast cells of
Japanese participants83 in the international HapMap Project;84 it was found that the expression of FADS1 was associated with single nucleotide polymorphisms (SNPs) of
FADS2.83 Moreover, they reported that both simvastatin, a
lipid-lowering drug,85 and GW3965, a LXR agonist,86
caused upregulation of FADS1 and FADS2 expression, but
rosiglitazone, a peroxisomal PPARc agonist87 did not induce any response. Transcription factors, such as peroxisomal PPAR and sterol regulatory element binding protein
(SREBP) are also important for the synthesis of lipids
and regulation of lipid metabolism to affect human health
and physiology.2,88 Interestingly, the putative binding sites
for transcription factors, such as SREBP and PPARc were
located at a highly conserved region existing in the
most significant SNPs of FADS2 associated with FADS1
expression.83 FADS2 intron 1 contained two insertion–
deletions observed depending on the difference of major
and minor alleles, and minor alleles showed higher induction of FADS genes with the addition of simvastatin and
GW3965,83 implying that the transcription factors are also
important for the regulation of lipid metabolism, as well as
interactive regulation between FADS1 and FADS2, and
that the types of alleles might be major determinants of the
sensitivity of statin therapy and the pattern of PUFA consumption.
CONCLUSIONS
UFA have been considered physiologically important
nutrients and a variety of desaturases are major enzymes in
the biosynthesis of fatty acids with important implications
for human health and development. SCD, catalyzing the
biosynthesis of MUFA has been to be involved in obesity,
insulin resistance, and skin disease (Table 1). FADS are a
group of enzyme isoforms that generate PUFA, and the
genes encoding FADS have been found to be related to
chronic diseases, such as cardiovascular disease, diabetes,
and cancer (Table 1). In addition, the physiological functions of SCD and its isoforms have been reported, and
novel functions of FADS genes and their alternative transcripts have been elucidated. Recent genetic and genomic
studies have also provided evidence that PUFA and FADS
genes are important for human health and regulation,
suggesting that the genes may have significant effects on
human health and lipid metabolism depending on human
physiological and nutritional conditions, and that SCD
might be relevant to insulin sensitivity even though the
study has not been repeated. In the near future, research
using more advanced molecular techniques may help to
provide more clues to clarify elusive relationships between
UFA and their associated genes. Consequently, it is ex-
pected that forthcoming PUFA studies will further elucidate the complicated physiology of PUFA in human health
and diseases.
ACKNOWLEDGMENT
This study was supported by 2013 Academic Research
Support Program in Gangneung-Wonju National University,
Republic of Korea.
AUTHOR DISCLOSURE STATEMENT
No competing financial interests exist.
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