Prostaglandins, Leukotrienes and Essential Fatty Acids 68 (2003) 145–150

Essential fatty acid synthesis and its regulation in mammals

M.T. Nakamura*, T.Y. Nara
Department of Food Science and Human Nutrition, University of Illinois at Urbana-Champaign, 905 S. Goodwin Avenue, Urbana, IL 61801, USA
Received 20 August 2002; accepted 5 September 2002

Abstract

The tissue content of highly unsaturated fatty acids (HUFA) such as arachidonic acid and docosahexaenoic acid is maintained in
a narrow range by feedback regulation of synthesis. Delta-6 desaturase (D6D) catalyzes the first and rate-limiting step of the HUFA
synthesis. Recent identification of a human case of D6D deficiency underscores the importance of this pathway. Sterol regulatory
element binding protein-1c (SREBP-1c) is a key transcription factor that activates transcription of genes involved with fatty acid
synthesis. We recently identified sterol regulatory element (SRE) that is required for activation of the human D6D gene by SREBP-
1c. Moreover, the same SRE also mediates the suppression of the D6D gene by HUFA. The identification of SREBP-1c as a key
regulator of D6D suggests that the major physiological function of SREBP-1c in liver may be the regulation of phospholipid
synthesis rather than triglyceride synthesis. Peroxisome proliferators (PP) induce fatty acid oxidation enzymes and desaturases in
rodent liver. However, the induction of desaturases by PP is slower than the induction of oxidation enzymes. This delayed induction
may be a compensatory reaction to the increased demand of HUFA caused by increased HUFA oxidation and peroxisome
proliferation in PP administration. Recent studies have demonstrated a critical role of peroxisomal b-oxidation in DHA synthesis,
and identified acyl CoA oxidase and D-bifunctional protein as the key enzymes.
r 2002 Elsevier Science Ltd. All rights reserved.

1. Introduction is altered in pathological conditions such as diabetes [7],

Highly unsaturated fatty acids (HUFA) such as
arachidonic acid and docosahexaenoic acid (DHA) are
essential for a variety of physiological functions [1]
including (1) skin integrity [2,3], (2) eicosanoid signaling
[4,5] and (3) vision and brain functions [6]. Mammals do
not have enzymes to synthesize HUFA from acetyl
CoA. However, mammals are capable of synthesizing
HUFA from precursor polyunsaturated fatty acids
(PUFA), 18:2n-6 and 18:3n-3 (Fig. 1). Thus, 18:2n-6
and 18:3n-3 are dietary essential. Tissue HUFA content
Abbreviations: CYP4A, cytochrome P450 4A; D5D, D5 desaturase;
D6D, D6 desaturase; DBP, D-bifunctional protein; DHA, docosahex-
aenoic acid; HUFA, highly unsaturated fatty acids; LBP, L-bifunc-
tional protein; PL, phospholipids; PP peroxisome proliferators;
PPARa, peroxisome proliferator activated receptor-a; PPRE, peroxi-
some proliferator response element; PUFA, polyunsaturated fatty
acids; SAOX, straight-chain acyl CoA oxidase; SCD, stearoyl CoA
desaturase (D9 desaturase); SRE, sterol regulatory element; SREBP,
sterol regulatory element binding protein; TG, Triglycerides
*Corresponding author. Tel.: +1-217-333-1267; fax: +1-217-265-
0925.
E-mail address: mtnakamu@uiuc.edu (M.T. Nakamura).
insulin resistance [8], peroxisome disorders [9,10], a
growth hormone excess [11,12], and alcoholism [13–15].
Also, bypassing synthetic pathway by supplying
n-3 or n-6 HUFA from a diet changes the ratio of n-3
and n-6 HUFA in tissues, and affects cellular functions
[16–23].
In a physiological condition, tissue HUFA content is
maintained in a narrow range by feedback regulation of
the synthetic pathway. The desaturation by delta-6
desaturase (D6D) is the first and rate-limiting step of the
HUFA synthesis [24]. A human case of D6D defect
showed a severe gastrointestinal malfunction and skin
abnormality [3]. The latter symptom was not completely
corrected by dietary supplementation of HUFA, under-
scoring the importance of the endogenous pathway of
HUFA synthesis [3]. The D6D activity and HUFA
synthesis are under strong control by dietary fats [20]
and other factors such as insulin [25], growth hormone
[12], inflammatory stimuli [26] and peroxisome prolif-
erators (PP) [27]. Until recently, little was known about
the regulatory mechanism of D6D. We succeeded in
cloning the D6D and delta-5 desaturase (D5D) genes
and found that the mRNA of D6D and D5D were low

0952-3278/03/$ - see front matter r 2002 Elsevier Science Ltd. All rights reserved.
PII: S 0 9 5 2 - 3 2 7 8 ( 0 2 ) 0 0 2 6 4 - 8
146 M.T. Nakamura, T.Y. Nara / Prostaglandins, Leukotrienes and Essential Fatty Acids 68 (2003) 145–150
n-6 n-3
18:2 (linoleic) α -linolenic)
18:3 (α
∆6 Desaturase
18:3 (γγ -linolenic) 18:4
Elongase
20:3 20:4
∆5 Desaturase
20:4 (arachidonic) 20:5 (EPA)
Elongase
24:5
∆6 Desaturase
24:6
Peroxisomal
β-oxidation
22:6 (DHA)
Fig. 1. Anabolic pathway of essential fatty acids.
when PUFA or HUFA was supplied from a diet, while
essential fatty acid deficient diets such as fat-free diet
and triolein (18:1n-9) diet induced the mRNA in rat
liver [28,29].
2. Sterol regulatory element binding protein-1c: a key
regulator of D6D gene expression
Sterol regulatory element binding proteins (SREBP)
were found as the factors that bind sterol regulatory
element (SRE) in the LDL receptor promoter [30].
SREBP have two isoforms, SREBP-1 and SREBP-2,
which are transcribed from different genes [31,32].
SREBP-1 has two subforms, SREBP-1c and SREBP-
1a, which are encoded from the same gene by alternative
promoter usage [33]. SREBP-2 mainly activates tran-
scription of genes involved with cholesterol synthesis
and metabolism, while SREBP-1 targets genes for fatty
acid synthesis [34]. The expression of SREBP-1a is high
in dividing cells such as cell lines, whereas SREBP-1c is
the major species in many differentiated cells including
hepatocytes [33]. SREBP are synthesized as a larger
precursor protein that is anchored to the endoplasmic
reticulum membrane. After proteolytic cleavage, the
amino terminal domain migrates to a nucleus and
activates target genes [34].
SREBP-1c activates entire genes of fatty acid synth-
esis in liver [35]. Target genes include acetyl CoA
synthase [36], acetyl CoA carboxylase [37], fatty acid
synthase [38], stearoyl CoA desaturase (SCD) [39],
elongase [40] and S14 [41]. Matsuzaka et al. reported
that D6D and D5D mRNA were also elevated in
transgenic mice overexpressing SREBP-1 [42]. We
recently identified SRE that is required for activation
of the human D6D gene by SREBP-1c [43]. The
presence of SRE in D6D is consistent with another
study reporting that the D6D mRNA was diminished in
diabetic rats and was restored by insulin administration
[44] because accumulating evidence indicates that
SREBP-1c also mediates the effect of insulin on
transcriptional activation of genes involved in fatty acid
synthesis [35,45,46].
SREBP-1c also mediates the PUFA inhibition of
genes involved with fatty acid synthesis such as SCD
[39,47], fatty acid synthase [48] and S14 [41]. HUFA
suppress the target gene transcription by reducing the
active form of SREBP-1c [41,48–51]. We found that the
SRE in the human D6D promoter also mediates the
suppression of the D6D gene by HUFA [43]. The
identification of SREBP-1c as a key regulator of D6D
suggests that the major physiological function of
SREBP-1c in liver may be the regulation of phospho-
lipid (PL) synthesis rather than triglyceride (TG)
synthesis because HUFA are mainly incorporated into
PL and are very poor substrates for TG synthesis
[12,52]. Indeed, Dobrosotskaya et al. recently reported
that phosphatidyl ethanolamine controls maturation of
SREBP in Drosophila cells, and proposed a hypothesis
that the primary role of SREBP in animals is to monitor
and maintain cell membrane composition [53]. A wide-
spread expression of SREBP-1c including in non-
lipogenic tissues [33] also supports this hypothesis.
Furthermore, CTP:phosphocholine cytidylyltransferase,
a key enzyme of phosphatidylcholine synthesis is also
regulated by SREBP [54].
PUFA suppress active form of SREBP-1c by three
different mechanisms. First, PUFA inhibits liver-X
receptor activation by acting as antagonistic ligands in
cell lines [51,55]. Second, HUFA decrease stability of
SREBP-1 mRNA in rat hepatocytes [50]. Third, HUFA
reduce nuclear form SREBP-1 in rat liver [48] and in
HEK 293 cells [49]. The mechanisms by which HUFA
reduce the SREBP-1 mRNA stability and the SREBP-1
processing are currently unknown.
3. Activation of D6D by peroxisome proliferators
Hypolipidemic PP such as fibrates and Wy14643
induce fatty acid oxidation enzymes, and in rodents,
cause peroxisome proliferation in liver [56]. These PP
effects are mediated by peroxisome proliferator acti-
vated receptor-a (PPARa), a transcription factor of
nuclear receptor family. PP and fatty acids act as
agonistic ligands of PPARa, which then activate
transcription of target genes by binding as a heterodimer
to a cis-element, peroxisome proliferator response
 M.T. Nakamura, T.Y. Nara / Prostaglandins, Leukotrienes and Essential Fatty Acids 68 (2003) 145–150
element (PPRE) [57,58]. Target genes of PPARa include
mitochondrial fatty acid oxidative enzymes [59], mito-
chondrial 3-hydroxy-3-methylglutaryl-CoA synthase
[60], cytochrome P450 4A (CYP4A) [61], straight-chain
acyl CoA oxidase (SAOX) and peroxisomal L-bifunc-
tional protein (LBP) [62]. Induction of fatty acid
oxidation and ketogenesis are impaired in PPARa-null
mice during starvation, resulting in hypothermia and
hypoglycemia, whereas these animals grow normally
when food is freely accessible [63–65]. These studies
demonstrated that PPARa plays a critical role in the
metabolic adaptation to starvation by inducing genes
for fatty acid oxidation.
Kawashima et al. first reported that fibrates increase
the activity of D6D and SCD in rats [27,66]. We found
that Wy14643 strongly induces the D6D mRNA in rat
liver (Nakamura and Nara, unpublished data). We also
identified PPRE that mediates the activation of the
human D6D promoter by Wy14643 in HepG2 cells
(Clarke and Nakamura, unpublished data). This induc-
tion of desaturases by PP poses a few paradoxes to be
resolved. First of all, PPARa in general induces genes of
fatty acid oxidation, while SREBP-1 induces genes of
fatty acid synthesis. To our knowledge, no gene that is
activated by both SREBP-1c and PP has been identified
with the exception of desaturases (D6D, SCD [39,67]
and probably D5D). Second, in spite of marked
induction (>10 fold) of the D6D activity and mRNA
in rat liver after PP administration, the composition of
HUFA (products of D6D/D5D pathway) in the liver
lipids did not increase. Instead, the HUFA composition
was remarkably well maintained [27,68] (Nakamura and
Nara unpublished data). Third, contrary to a rapid
induction of PPARa responsive genes for fatty acid
oxidation such as SAOX, carnitine palmitoyl transfer-
ase-1, LBP and CYP4A, the induction of the D6D and
D5D mRNA took longer to reach the maximum
induction (Nakamura and Nara unpublished data).
The SCD-1 gene, in which both SRE and PPRE are
identified, also showed a delayed induction by clofibrate
in mouse liver [67]. Moreover, the induction of SCD-1
mRNA was inhibited by cycloheximide, suggesting that
the induction may be dependent on protein synthesis
[67].
Taken together, in addition to the direct activation by
PPARa binding to PPRE in the D6D promoter, other
mechanisms are likely to be involved in the induction of
D6D gene by PP. Because PP induce enzymes for fatty
acid oxidation both in peroxisome and mitochondria
[56], PP administration is likely to increase the
degradation of HUFA. In addition, the requirement of
HUFA for membrane PL would be increased by PP
administration, which induces proliferation of peroxi-
some and enlargement of liver in rodents [27,56]. Thus,
the delayed induction of desaturases by PP may be a
compensatory reaction to the increased demand of
147
HUFA caused by increased HUFA oxidation and
peroxisome proliferation.
4. Synthesis of DHA
Voss et al. first reported that 24:5n-3 was desaturated
to 24:6 and then was readily retroconverted to DHA in
rat liver [69]. Because the presence of delta-4 desaturase
had never been demonstrated in mammals, they
proposed that eicosapentaenoic acid was elongated
and desaturated at delta-6 position to 24:6 in micro-
somes and then b-oxidized to DHA in peroxisomes
(Fig. 1). The peroxisomal b-oxidation is carried out by
three enzymes, acyl CoA oxidase, bifunctional protein
and 3-ketoacyl CoA thiolase. Each of these enzymes has
isozymes [56]. Studies with human skin fibroblast
showed that either SAOX or D-bifunctional protein
(DBP) deficiency greatly reduced DHA synthesis, but it
did not completely abolish the synthesis [70,71]. An in
vivo study using SAOX-null mice showed the same
results as the studies with fibroblast [72]. These studies
have demonstrated a critical role of peroxisomal b-
oxidation in DHA synthesis, and suggest that SAOX
and DBP play the major role in DHA synthesis, but
other peroxisomal isozymes can catalyze the reaction in
a lesser degree. It is yet to be determined whether the
final desaturation in DHA synthesis is catalyzed by the
same D6D that catalyzes the first step or by a D6D
isozyme.
Peroxisomes play the major role in the oxidation of
very long chain fatty acids (C > 20) [73]. Therefore,
peroxisomes are likely to be involved in both synthesis
and oxidation of DHA. It is currently unknown how
these opposing pathways are carried out and regulated
in the same organelle.
5. Concluding remarks
Significant advance has been made recently in under-
standing the regulatory mechanisms of HUFA synthesis
in mammals.
(1) A human case of D6D deficiency demonstrated the
importance of endogenous HUFA synthesis in
various physiological functions.
(2) SREBP-1c mediates the feedback regulation of
D6D gene by PUFA. This finding suggests
that the major role of SREBP-1c in liver may be
the regulation of fatty acid synthesis for membrane
PL.
(3) PP induce mRNA of fatty acid oxidation enzymes
prior to the desaturase mRNA. This delayed
induction of desaturases may be a compensatory
reaction to the increased demand of HUFA caused
148 M.T. Nakamura, T.Y. Nara / Prostaglandins, Leukotrienes and Essential Fatty Acids 68 (2003) 145–150
by increased HUFA oxidation and peroxisome
proliferation.
(4) Peroxisomal enzymes, SAOX and DBP, play the
major but not sole role in the DHA synthesis from
24:6.
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