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-6 Desaturase Expression and Its Role in the Polyunsaturated Fatty Acid Inhibition of Fatty Acid Synthase Gene Expression in Mice1
Graduate Program of Nutritional Sciences and the Institute for Cellular and Molecular Biology, The University of Texas, Austin, TX 78712
2To whom correspondence should be addressed.
 |
ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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-6
desaturase pathway was essential for the production of the fatty acid
regulator of gene expression. To address this hypothesis, male BALB/c
mice (n = 8/group) were fed for 5 d a high
glucose, fat-free diet (FF) or the FF plus 50 g/kg 18:2(n-6) with
and without eicosa-5,8,11,14-tetraynoic acid (ETYA) (200 mg/kg diet), a
putative inhibitor of the -6 desaturase pathway. ETYA had no effect
on food intake or weight gain, but it completely prevented 18:2(n-6)
from suppressing the hepatic abundance of fatty acid synthase mRNA.
ETYA ingestion was associated with a decrease in the hepatic content of
20:4(n-6) and an increase in the amount of 18:2(n-6). The fatty acid
composition changes elicited by ETYA were accompanied by a decrease in
the enzymatic activity of -6 desaturase. Interestingly, the hepatic
abundance of -6 desaturase mRNA was actually induced by ETYA one- to
twofold. When the product of -6 desaturase, i.e., 18:3(n-6), was
added to the ETYA plus 18:2(n-6) diet, the hepatic content of 20:4(n-6)
was normalized. In addition, 18:3(n-6) consumption reduced the level of
hepatic -6 desaturase mRNA by 50% and completely prevented the
increase in fatty acid synthase mRNA that was associated with ETYA
ingestion. Apparently, -6 desaturation is an essential step for the
PUFA regulation of the fatty acid synthase gene transcription. Finally,
the suppression of -6 desaturase by PUFA and its induction by ETYA
suggest that the -6 desaturase gene may be regulated by two
different lipid-dependent mechanisms.
KEY WORDS: • -6 desaturase • fatty acid synthase • ETYA • linoleic acid • mice
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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, Jump et al. 1994
, Ntambi 1991, Xu et al. 1999
). On the other hand, these genes are not inhibited by
saturated or monounsaturated fatty acids. Such transcriptional
regulation by polyunsaturated fats does not require eicosanoid
synthesis (Clarke et al. 1997
, Flick et al. 1977
). Moreover, the fatty acid regulation of lipogenic genes
does not directly involve a peroxisome proliferator-activated
receptor (PPAR)-mediated mechanism (Clarke et al. 1997
,
Ren et al. 1997
). Recently, we discovered that the
dietary PUFA suppression of hepatic fatty acid synthase transcription
was associated with a 70% reduction in the nuclear content and mRNA
abundance of the transcription factor, sterol regulatory element
binding protein-1 (Xu et al. 1999
). Moreover, PPAR
activation by WY-14,634 was also found to reduce the hepatic expression
of sterol regulatory element binding protein-1, and this was
accompanied by a decrease in the hepatic abundance of fatty acid
synthase mRNA (Xu et al. 1999
). In spite of improved
understanding of which nuclear transcription factors may be regulated
by PUFA, the intracellular signaling mechanism that is responsible for
the PUFA regulation of lipogenic gene transcription remains unknown.
Several years ago we discovered that feeding
eicosa-5,8,11,14-tetraynoic acid (ETYA), which is an alkyne derivative
of 20:4(n-6), resulted in an increase in the hepatic content of
18:2(n-6) and a significant decrease in the hepatic content of
20:4(n-6) (Clarke and Clarke 1982
). In addition to
affecting 18:2(n-6) metabolism, ETYA blocked the ability of dietary
18:2(n-6) to suppress the activity of hepatic acetyl CoA carboxylase
and fatty acid synthase (Clarke and Clarke 1982
). The
fatty acid metabolite profile of the liver indicated that ETYA
interfered with the conversion of 18:2(n-6) to 20:4(n-6) by inhibiting
the activity of -6 desaturase, which catalyzes the first and
rate-limiting step of the pathway (Sprecher 1981
).
Moreover, the data suggested that a metabolite of the fatty acid
desaturase pathway was responsible for the inhibition of lipogenic gene
expression. However, there was no measure of -6 desaturase activity
nor were there any measures of fatty acid synthase gene expression.
Recently, we reported the cloning of the open reading frame for the
mouse and human -6 desaturase (Cho et al. 1999
). This
new tool provided us the opportunity to examine the effect of dietary
ETYA and polyunsaturated fats on the expression of -6 desaturase and
to correlate changes in -6 desaturase with alterations in the
expression of hepatic lipogenic enzymes, i.e., fatty acid synthase.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Male BALB/c mice, 3–4 wk old, were purchased from Harlan Labs
(Indianapolis, IN) and fed a high glucose, fat-free diet
(Table 1
). After 10 d, mice (8 per diet group) were randomly allotted to
one of the following five dietary treatments: 1)
fat-free, high glucose (Table 1)
; 2) fat-free
plus ETYA (gift from Hoffman-La Roche, Nuttley, NJ);
3) fat-free diet supplemented with 18:2(n-6) (99%
purity, Sigma Chemical, St. Louis, MO); 4) fat-free
diet supplemented with 18:2(n-6) plus ETYA; and 5)
fat-free diet supplemented with the combination of 4% 18:2(n-6)
and 1% 18:3(n-6) (99% purity, Nu-Chek-Prep, Elysian, MN) plus ETYA.
ETYA was provided at 200 mg/kg diet. The 18:2(n-6) supplement was
provided as 50 g/kg diet; and the combination of 18:2 and 18:3(n-6) was
supplemented as 40 g 18:2(n-6) and 10 g 18:3(n-6)/kg diet.
The mice were fed the respective diets for 5 d. The mice were
killed at the end of the dark cycle between 0800 and 0900 h;
livers were removed and utilized for RNA extraction and microsomal
membrane preparation. The protocol was approved by the institutional
Animal Care and Use Committee.
|
Total hepatic RNA was extracted using the guanidinium
thiocyanate-phenol procedure of Chomczynski and Sacchi (1987)
. The relative mRNA abundance for -6 desaturase, fatty
acid synthase and ß-actin was determined by Northern analysis
(Clarke et al. 1990
). Briefly, the RNA was size
fractionated by agarose gel electrophoresis and subsequently
transferred to Zeta-Probe GT nylon membrane (Bio-Rad, Hercules, CA)
by electroblotting. The RNA was fixed to the membrane by UV-cross
linking, and the abundance of each transcript of interest was
determined by sequential hybridization using specific cDNA probes that
were radiolabeled by random priming (Gibco BRL, Baltimore, MD) with
-32P-dCTP (Amersham, Arlington Heights, IL).
Prehybridization, hybridization and stringency wash conditions were
conducted at 40°C as described by Clarke et al. (1990)
. After the membrane was blotted dry, it was exposed to
Kodak (Rochester, NY) X-Omat AR film, and the resulting
autoradiographic signal was quantified using the AMBIS Optical Imaging
System (AMBIS, San Diego, CA). Data are expressed as arbitrary optical
units and normalized to ß-actin.
-6 Desaturase enzymatic activity measures.
The activity of hepatic -6 desaturase was determined in freshly
isolated microsomes using the procedure of Mimouni and Poisson (1992)
. Microsomes were isolated by mincing and homogenizing
liver (1 g/4 mL) in 0.25 mol/L sucrose containing 50 mmol/L potassium
phosphate, pH 7.4. The homogenate was centrifuged for 10 min at 10,000
x g. The resulting supernatant was centrifuged at
100,000 x g for 60 min, and the resulting
microsomal pellet was suspended in homogenization buffer to a
concentration of 20 g protein/L. Enzymatic activity was determined
using a 1-mL assay mixture that contained the following: 72 mmol/L
potassium phosphate (pH 7.4), 4.8 mmol/L MgCl2, 0.5 mmol/L
coenzyme A, 3.6 mmol/L ATP, 1.2 mmol/L NADH and 50 nmol of
1-14C-18:2(n-6). The reaction was started with the addition
of 3 mg of microsomal protein, and the mixture was incubated for 5 min
at 37°C. The reaction rate was linear during this period. The
reaction was stopped by adding 1 mL ethanolic KOH, 200 g/L. Total
lipids were subsequently saponified by heating the ethanolic KOH
mixture for 90 min at 75°C. The mixture was then acidified with 8
mol/L HCl and the fatty acids were extracted with hexane. After their
extraction, the fatty acids were converted to methyl ester and
extracted with petroleum ether. The distribution of radioactivity
between the 18:2(n-6) substrate and the 18:3(n-6) product of -6
desaturase was determined using TLC with silica gel G plates
impregnated with AgNO3 (10 g/100 g gel) (Garg et al. 1992
). Enzyme activity is expressed as nmol substrate converted
to product/(mg protein · min).
Microsomal fatty acid composition.
The fatty acid composition of the hepatic microsomes was determined by
extracting the total lipid, isolating total phospholipids by TLC,
methylating the phospholipids and determining the fatty acid
composition of the phospholipids by gas-liquid chromatography using
a Supelco SP-2380 capillary column (Odin et al. 1987
).
Fatty acid methyl ester (FAME) peaks were identified using a standard
mixture of FAME, and the peak areas were quantified using a 17:0
internal standard.
Statistical analyses.
Mean differences in liver microsomal total phospholipid fatty acid composition were determined using Tukey’s test after two-way ANOVA. Mean differences for enzymatic activity and mRNA abundance were analyzed by Fisher’s least-square difference test after ANOVA. Differences were considered significant at P < 0.05.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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that contained ETYA (200 mg/kg diet)
reduced -6 desaturase enzymatic activity 65% (P < 0.05) (data not shown). The recent cloning of a -6 desaturase
specific cDNA (Cho et al. 1999
) provided us the
opportunity to determine in a second dietary study whether ETYA
ingestion suppressed -6 desaturase enzyme activity by inhibiting the
enzyme directly or by suppressing -6 desaturase gene expression. As
observed in our preliminary study, supplementing the diet with ETYA
(200 mg/kg) significantly (P < 0.001) reduced hepatic
-6 desaturase enzymatic activity 80–90% (Fig. 1
). Like dietary ETYA, supplementing the fat-free diet with 18:2(n-6)
also significantly (P < 0.05) reduced the hepatic
activity of -6 desaturase (Fig. 1)
. Northern analysis revealed that
the decrease in enzymatic activity associated with the ingestion of
18:2(n-6) was paralleled by a significant (P < 0.05)
reduction in the hepatic abundance of -6 desaturase mRNA (Fig. 2
). However, the marked decrease in hepatic -6 desaturase enzymatic
activity resulting from the ingestion of ETYA was not accompanied by a
decrease in the hepatic abundance of -6 desaturase mRNA (Fig. 2)
. In
fact, ETYA supplementation to either the fat-free or the 18:2(n-6)
diet induced the hepatic abundance of -6 desaturase mRNA by 100 and
200%, respectively (Fig. 2)
. On the other hand, replacing part of the
18:2(n-6) with 18:3(n-6), which is the fatty acid product of -6
desaturase, prevented the rise in -6 desaturase mRNA abundance
associated with ETYA ingestion (Fig. 2)
. The observations that ETYA
suppressed -6 desaturase enzyme activity while it increased the
hepatic content of -6 desaturase mRNA suggested that ETYA functioned
as a direct inhibitor of -6 desaturase enzyme. When -6 desaturase
enzymatic activity was measured in the presence of varying
concentrations of albumin-bound ETYA, ETYA inhibited -6
desaturase enzymatic activity in a dose-dependent manner
(Fig. 3
).
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-6 desaturase mRNA, its effect on lipogenic gene expression
(i.e., hepatic content of fatty acid synthase mRNA) was also evaluated.
Consistent with our earlier studies (Clarke et al. 1990
,
Jump et al. 1994
, Xu et al. 1999
),
supplementing the high glucose diet with the 18:2(n-6) significantly
reduced the hepatic content of fatty acid synthase mRNA (Fig. 4
). On the other hand, supplementing the high glucose, fat-free diet
with ETYA did not reduce the hepatic abundance of fatty acid synthase
(Fig. 4)
. More importantly, supplementing the 18:2(n-6) diet with ETYA
completely prevented the characteristic decrease in hepatic abundance
of fatty acid synthase mRNA that is elicited by the consumption of
18:2(n-6). ETYA also prevented 11,14,17–20:3(n-3) from inhibiting the
expression of hepatic fatty acid synthase (data not shown). On the
other hand, when the fatty acid product of -6 desaturase, i.e.,
18:3(n-6), was included in the diet with 18:2(n-6) and ETYA, the ETYA
inhibition of -6 desaturase was by-passed as indicated by the
normalized 20:4(n-6) content of the microsomes, and the reestablishment
of a 50% decrease in hepatic fatty acid synthase mRNA abundance
(Table 2
and Fig. 4
). The increase in hepatic 20:3(n-6) and 20:4(n-6) resulting
from the ingestion of 18:3(n-6) indicated that ETYA did not interfere
with fatty acid elongation or the activity of -5 desaturase.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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). This metabolite crossover pattern suggested that
ETYA inhibited the activity of either -6 or -5 desaturase.
Because there was no observable change in the hepatic content of
20:3(n-6), we hypothesized that the decrease in hepatic content of
20:4(n-6) was due to the fact that ETYA suppressed the expression of
-6 desaturase. In this report, the hepatic expression of -6
desaturase has been examined at the level of enzyme activity and mRNA
abundance. Interestingly, although ingestion of ETYA reduced -6
desaturase enzymatic activity nearly 90% (Fig. 2)
, this was not
paralleled by a decrease in -6 desaturase mRNA abundance. In fact,
just the opposite occurred, i.e., hepatic abundance of -6 desaturase
mRNA increased one- to twofold in response to ETYA (Fig. 2)
. An
increase in -6 desaturase mRNA content in the face of a 90%
suppression in -6 desaturase enzyme activity strongly suggested that
ETYA was a direct inhibitor of the -6 desaturase enzyme. As can be
seen in Figure 3
, when -6 desaturase enzyme activity was measured in
the presence of varying concentrations of ETYA, -6 desaturase
enzymatic activity was reduced. The amount of ETYA required to achieve
half-maximum inhibition was estimated to be 1.0 mmol/L, which is
~300 µg/g liver. When one considers that the average
daily intake of ETYA was ~500–750 µg/d, and that the
average mouse liver weighed 1 g, then the direct suppression of
-6 desaturase by ETYA observed in our enzymatic assays appears to be
consistent with the physiologic outcome.
Although the inhibition of -6 desaturase activity appears to result
from the direct inhibition of the enzyme by ETYA, the increase in -6
desaturase mRNA abundance may be related to the fact that ETYA is a
ligand activator of the transcription factor PPAR (Forman et al. 1997
, Kliewer et al. 1997
, Tontonoz et al. 1994
, Varanasi et al. 1996
). PPAR are a
family of transcription factors that consists of several isoforms
including , 
, 
-1 and -2 (Clarke et al. 1999
,
Forman et al. 1997
, Kliewer et al. 1997
,
Staels et al. 1998
, Tontonoz et al. 1994
). The dominant isoform varies with tissue type. In the
liver, the predominant form of PPAR is PPAR. Like all members of the
steroid-like receptor family of transcription factors (e.g.,
thyroid hormone receptor and vitamin D-3 receptor), the binding of
PPAR to its DNA recognition sequence, and the consequential change
in transcription of PPAR-regulated genes, is greatly dependent upon
the binding of specific ligands to the ligand-binding domain of
PPAR (Clarke et al. 1999
, Staels et al. 1998
). In this case, we propose that the increase in hepatic
abundance of -6 desaturase mRNA resulting from ETYA ingestion is the
consequence of ligand activation of PPAR by ETYA. The activation
PPAR subsequently enhances the binding of PPAR to its DNA
recognition sequence, which in turn induces the transcription of the
-6 desaturase gene. Under circumstances in which the PPAR
activator is not a direct inhibitor of the -6 desaturase enzyme per
se, the predicted outcome of this PPAR-dependent induction of the
-6 desaturase gene expression would be an increase in -6
desaturase enzyme activity. Consistent with this hypothesis,
Kawashima et al. (1990)
reported that feeding rats
fibrate, a PPAR specific ligand, induced -6 desaturase enzyme
activity several fold. In addition, a search of the genomic sequence
for the human -6 desaturase has revealed the presence of a candidate
PPAR response element within the 5'-flanking region of the -6
desaturase gene (Tang and Clarke, unpublished data). However, the
functionality of this element remains to be determined. The apparent
involvement of PPAR as a positive regulator of -6 desaturase gene
expression presents an interesting mechanistic conflict because dietary
PUFA, which are well established as ligand activators of PPAR
(Forman et al. 1997
, Kliewer et al. 1997
), reduce the mRNA abundance and enzymatic activity of
hepatic -6 desaturase (Figs. 1
, 2
; Cho et al. 1999
).
One possibility is that -6 desaturase gene transcription is governed
by two different and competing PPAR. Alternatively, the -6
desaturase gene may be regulated by a PPAR-dependent
(up-regulation) and -independent (down-regulation) mechanism. In this
scenario, the activation of PPAR by PUFA is less responsive than is
the inhibitory mechanism. Although the mechanism of gene control is yet
to be established, the -6 desaturase gene appears to provide a
unique single-gene model to define the regulatory mechanisms by
which PPAR ligands can function both as inducers and suppressers of
gene transcription.
Aside from the observation that PPAR may regulate -6 desaturase gene
expression in a very unique way, the ETYA inhibition of 20:4(n-6)
synthesis has revealed a very important clue to our understanding of
how dietary 18:2(n-6) and 18:3(n-3) fatty acids inhibit the expression
of lipogenic genes. Specifically, our data indicate that -6
desaturation of (n-6) and (n-3) PUFA is required for these fatty acids
to suppress the expression of genes encoding lipogenic enzymes (e.g.,
fatty acid synthase). This conclusion is supported by two observations.
First, supplementing the 18:2(n-6) diet with ETYA completely prevented
the reduction in fatty acid synthase mRNA abundance that is
characteristically elicited by 18:2(n-6) (Fig. 4
; Jump and Clarke 1999
). This response of fatty acid synthase to ETYA was
not due to an induction of fatty acid synthase gene expression by ETYA
per se as can be seen by the failure of ETYA to increase the level of
fatty acid synthase mRNA when the ETYA was provided with the
fat-free diet (Fig. 4)
. Second, when part of the 18:2(n-6) was
replaced with the -6 desaturase product, 18:3(n-6), fatty acid
synthase gene expression was completely reinstated (Fig. 4)
. In
addition, 18:3(n-6) supplementation replenished the 20:4(n-6) pool that
had been depleted previously by the ETYA inhibition of -6
desaturase. The fact that 18:3(n-6) conversion to 20:4(n-6) was not
impaired by ETYA indicates that the -5 desaturase was unaffected by
ETYA. Although the data do not allow us to determine whether the fatty
acid inhibitor of lipogenic gene expression is 18:3(n-6) or an
elongated/desaturated product, the results clearly demonstrate that
-6 desaturation is an essential step in the control process.
In conclusion, the ingestion of PUFA from the (n-6) and (n-3) families
uniquely suppresses the transcription of hepatic lipogenic and
glycolytic genes (Jump and Clarke 1999
). In contrast,
saturated and monounsaturated fatty acids have no inhibitory effect on
lipogenic gene expression. In spite of the progress that has been made
toward identifying transcription factors and cis-acting
elements affected by polyunsaturated fats, little information is
available regarding the nature of the intracellular signal derived from
these inhibitory fatty acids. However, in this report, we demonstrate
that the -6 desaturase pathway plays a pivotal role in the synthesis
of an (n-6) or (n-3) fatty acid metabolite that is required for the
inhibition of fatty acid synthase gene transcription. The next step
will be to determine whether -5 desaturation is required for the
PUFA suppression of lipogenic gene transcription.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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3 Abbreviations used: ETYA, eicosa-5,8,11,14-tetraynoic acid; FAME, fatty acid methyl esters; PPAR, peroxisome proliferator-activated receptor; PUFA, polyunsaturated fatty acids.
Manuscript received November 4, 1999. Initial review completed December 24, 1999. Revision accepted February 18, 2000.
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Y. Wang, D. Botolin, B. Christian, J. Busik, J. Xu, and D. B. Jump Tissue-specific, nutritional, and developmental regulation of rat fatty acid elongases J. Lipid Res., April 1, 2005; 46(4): 706 - 715. [Abstract] [Full Text] [PDF]
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C. Tang, H. P. Cho, M. T. Nakamura, and S. D. Clarke Regulation of human {Delta}-6 desaturase gene transcription: identification of a functional direct repeat-1 element J. Lipid Res., April 1, 2003; 44(4): 686 - 695. [Abstract] [Full Text] [PDF]
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 J. Xu, H. Cho, S. O'Malley, J. H. Y. Park, and S. D. Clarke Dietary Polyunsaturated Fats Regulate Rat Liver Sterol Regulatory Element Binding Proteins-1 and -2 in Three Distinct Stages and by Different Mechanisms J. Nutr., November 1, 2002; 132(11): 3333 - 3339. [Abstract] [Full Text] [PDF]
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S. D. Clarke Polyunsaturated Fatty Acid Regulation of Gene Transcription: A Molecular Mechanism to Improve the Metabolic Syndrome J. Nutr., April 1, 2001; 131(4): 1129 - 1132. [Abstract] [Full Text]
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 J. Xu, M. Teran-Garcia, J. H. Y. Park, M. T. Nakamura, and S. D. Clarke Polyunsaturated Fatty Acids Suppress Hepatic Sterol Regulatory Element-binding Protein-1 Expression by Accelerating Transcript Decay J. Biol. Chem., March 23, 2001; 276(13): 9800 - 9807. [Abstract] [Full Text] [PDF]
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