Recent Advances in Nutritional Sciences
Polyunsaturated Fatty Acid and potentially in cardiomyocytes and cells (1,2). Lower
tissue lipids are associated with improvements in the metabolic
Regulation of Gene Transcription: A syndrome, such as increased insulin sensitivity (1,3). PUFA
Molecular Mechanism to Improve elicit their effects by coordinately suppressing lipid synthesis in
the liver, up-regulating fatty acid oxidation in liver and skel-
the Metabolic Syndrome1,2 etal muscle and increasing total body glycogen storage (3– 8).
-6 Desaturation of 18:2(n-6) and 18:3(n-3) is required for
Steven D. Clarke3 this “repartitioning” of metabolic fuel (9), and on a carbon-
Graduate Program of Nutrition and the Institute of Cell and
for-carbon basis, (n-3) fatty acids are more potent than (n-6)
Molecular Biology, The University of Texas at Austin, Austin,
fatty acids. The repartitioning activity of PUFA, particularly
Texas 78712 (n-3) PUFA, has been observed in humans as well as various
animal models (3,10 –13). Unfortunately, the amount of (n-6)
ABSTRACT This review addresses the hypothesis that and (n-3) and the best (n-6)-to-(n-3) ratio required for opti-
polyunsaturated fatty acids (PUFA), particularly those of the mum metabolic beneﬁt are unknown. However, as little as 2–5
(n-3) family, play pivotal roles as “fuel partitioners” in that g of 18:3(n-3) or 20:5 and 22:6(n-3) lower blood triglyceride
they direct fatty acids away from triglyceride storage and concentrations and reduce the risk of fatal ischemic heart
toward oxidation, and that they enhance glucose ﬂux to disease (12,13). Some of the beneﬁcial effects of PUFA are due
to changes in membrane fatty acid composition and subse-
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glycogen. In doing this, PUFA may protect against the ad-
verse symptoms of the metabolic syndrome and reduce the quent alterations in hormonal signaling (1). However, fatty
risk of heart disease. PUFA exert their beneﬁcial effects by acids themselves exert a direct, membrane-independent inﬂu-
up-regulating the expression of genes encoding proteins ence on molecular events that governs gene expression. It is
involved in fatty acid oxidation while simultaneously down- the regulation of gene expression by dietary fats that we
regulating genes encoding proteins of lipid synthesis. PUFA believe has the greatest impact on the development of insulin
govern oxidative gene expression by activating the tran- resistance and its related pathophysiologies (i.e., the metabolic
scription factor peroxisome proliferator-activated receptor syndrome). More importantly, determination of the cellular
. PUFA suppress lipogenic gene expression by reducing and molecular mechanisms regulated by PUFA may identify
the nuclear abundance and DNA-binding afﬁnity of tran- novel sites for pharmacological intervention.
scription factors responsible for imparting insulin and car-
bohydrate control to lipogenic and glycolytic genes. In par- PUFA Induction of Lipid Oxidation: The Role of
ticular, PUFA suppress the nuclear abundance and Peroxisome Proliferator-activated Receptor . One of
expression of sterol regulatory element binding protein-1 the ﬁrst steps in the PUFA-dependent repartitioning of met-
and reduce the DNA-binding activities of nuclear factor Y, abolic fuels involves an immediate reduction in the production
Sp1 and possibly hepatic nuclear factor-4. Collectively, the of hepatic malonyl coenzyme A (CoA) (14). Malonyl-CoA is
studies discussed suggest that the fuel “repartitioning” and a negative metabolite effector of carnitine palmitoyltransferase
gene expression actions of PUFA should be considered (15). Consequently, a PUFA-mediated decrease in hepatic
among criteria used in deﬁning the dietary needs of (n-6) malonyl-CoA favors fatty acid entry into the mitochondria
and (n-3) and in establishing the dietary ratio of (n-6) to (n-3) and peroxisomes and leads to enhanced fatty acid oxidation
needed for optimum health beneﬁt. J. Nutr. 131: 1129 –1132, (15). Whether PUFA suppress malonyl-CoA levels in skeletal
2001. muscle and heart remains to be determined, but such a mech-
anism would be consistent with the higher rates of fatty acid
KEY WORDS: ● sterol regulatory element binding protein oxidation observed in humans and animals fed diets rich in
● transcription ● fatty acids ● diabetes
The reduction in hepatic malonyl-CoA is paralleled by a
PUFA-dependent induction of genes encoding proteins involved
Dietary (n-6) and (n-3) polyunsaturated fatty acids in fatty acid oxidation and ketogenesis (3,4,7). These changes in
(PUFA)4 reduce triglyceride accumulation in skeletal muscle gene transcription occur too quickly to be explained simply by
altered hormone signaling resulting from modiﬁcations of the
membrane lipid environment. Rather, the changes are more
Supported by National Institutes of Health Grants DK-53872 and HD-37133 consistent with the idea that PUFA directly (e.g., ligand binding)
and by the sponsors of the M. M. Love Chair of Nutritional, Cellular, and Molecular regulate the activity or abundance of a nuclear transcription
Sciences. factor. In 1990, PPAR , a novel lipid-activated transcription
Manuscript received 9 January 2001.
To whom correspondence should be addressed at 115 Gearing Building, factor, was cloned (16). PPAR is a member of the steroid
The University of Texas, Austin, TX 78712. E-mail: firstname.lastname@example.org receptor superfamily, and like other steroid receptors, it possesses
Abbreviations used: CoA, coenzyme A; PUFA, polyunsaturated fatty acids; a DNA-binding domain and a ligand-binding domain (7,8,16).
PPAR, peroxisome proliferator-activated receptor; SREBP-1, sterol regulatory
element binding protein-1; NF-Y, nuclear factor Y; HNF-4, hepatic nuclear fac- The interaction of PPAR with its DNA recognition site is
tor-4. markedly enhanced by ligands such as the hypotriglyceridemic
0022-3166/01 $3.00 © 2001 American Society for Nutritional Sciences.
CoA desaturase and the -6 and -5 desaturases (4 – 6,24,25).
The discovery of PPAR led quickly to the idea that PPAR
was a “master switch” transcription factor that was targeted by
PUFA to coordinately suppress genes encoding proteins of
lipid synthesis and to induce genes encoding proteins of lipid
oxidation. This attractive hypothesis was strengthened by re-
ports that potent pharmacological activators of PPAR mod-
estly reduced lipogenic gene transcription (4,20). However,
PPAR does not interact with PUFA response regions iden-
tiﬁed in four different genes (3,4,6,9). Moreover, PUFA con-
tinue to suppress the transcription of hepatic lipogenic genes
in PPAR / mice (26). Thus, the inhibition of lipogenic
gene transcription associated with PPAR activation is indi-
rect and may simply reﬂect the PPAR -dependent induction
of the -6 desaturase pathway (9,27).
PUFA response sequences have been well characterized in
only three genes: fatty acid synthase, S14 and L-type pyruvate
FIGURE 1 Nuclear mechanism for polyunsaturated fatty acids kinase (3,4,20,28,29). The rat fatty acid synthase gene con-
(PUFA) regulation of gene expression. FA, fatty acids; NF-Y, nuclear tains two independent PUFA regulatory sequences that are
factor Y; PPAR, peroxisome proliferator-activated receptor; PPRE, per- located between 118 and 43 and between 7250 and
oxisome proliferator-activated receptor response element; Sp1, stimu- 7035 (M. Teran-Garcia and S. D. Clarke, unpublished data).
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latory protein 1; SREBP-1, sterol regulatory element binding protein-1; Approximately 65 and 35% of the PUFA control can be
TG, triglycerides. attributed to the proximal and distal elements, respectively.
Interestingly, the proximal PUFA response region of the fatty
acid synthase gene has characteristics that are very similar to
ﬁbrate drugs, conjugated linoleic acid and PUFA (17,18). In the PUFA response region of the S14 gene ( 220 to 80),
general, PPAR activation leads to the induction of several whereas the distal PUFA response region of the fatty acid
hepatic, cardiac and skeletal muscle genes encoding proteins synthase has similarities to the L-type pyruvate kinase PUFA
involved in lipid transport, oxidation and thermogenesis, includ- response region ( 160 to 97) (4).
ing carnitine palmitoyltransferase, peroxisomal acyl-CoA oxidase The proximal PUFA response region of the fatty acid
and uncoupling protein-3 (3,19,20). The (n-3) PUFA are more synthase gene imparts insulin responsiveness to the gene and
potent than the (n-6) PUFA as in vivo activators of PPAR contains DNA-binding sites for sterol regulatory element
(10 –13), but neither family of PUFA is a particularly strong binding protein-1 (SREBP-1), upstream stimulatory factor
PPAR activator. However, PUFA metabolites such as eico- (USF), Sp1 and nuclear factor Y (NF-Y) (20,29). The nuclear
sanoids or oxidized fatty acids have one to two orders of magni- abundance of USF and its DNA-binding activity is unaffected
tude greater afﬁnity for PPAR and are consequently far more by dietary PUFA (20). In contrast, PUFA rapidly reduce the
potent transcriptional activators of PPAR -dependent genes nuclear content of hepatic SREBP-1, and this is associated
(21). with a decrease in the rate of fatty acid synthase and S14 gene
The importance of PPAR to overall glucose and fatty acid transcription (20,29 –31). SREBP are a family of transcription
homeostasis has been clearly demonstrated in PPAR knock- factors (i.e., SREBP-1a, 1c and 2) that were ﬁrst isolated as
out mice (4,22). Because PPAR / mice lack the ability to a result of their properties for binding to the sterol regulatory
increase rates of fatty acid oxidation during periods of food element (32,33). SREBP-2 is a regulator of genes encoding
deprivation, they develop characteristics of adult-onset diabe- proteins involved in cholesterol metabolism (32,33). SREBP-1
tes, including fatty livers, elevated blood triglyceride concen- exists in two forms: 1a and 1c. SREBP-1a is the dominant form
trations and hyperglycemia (22). The essentiality of PPAR to in cell lines and is a regulator of genes encoding proteins
lipid oxidation was further underscored when hyperglycemia involved in both lipogenesis and cholesterogenesis. SREBP-1c
was found to suppress PPAR expression, induce PPAR constitutes 90% of the SREBP-1 found in vivo and is a
expression, increase -cell and cardiomyocyte lipids and ac- determinant of lipogenic gene transcription (32,33).
celerate cell death (23). Such “lipotoxicity” may be a contrib- SREBP-1 is synthesized as a 125-kDa precursor protein that
uting factor to the complications of non–insulin-dependent is anchored in the endoplasmic reticulum membrane (32,33).
diabetes (23). Clearly, PPAR is emerging as a pivotal player Proteolytic release of the 68-kDa mature SREBP-1 occurs in
in both fatty acid and glucose metabolism. More important, its the Golgi system, and movement of SREBP-1 from the endo-
regulation by PUFA, particularly (n-3) PUFA and possibly plasmic reticulum to the Golgi requires the trafﬁcking protein
conjugated linoleic acid (18), may offer an explanation for the SREBP cleavage-activating protein (33). Once released, ma-
reported beneﬁts of these fatty acids in protecting individuals ture SREBP-1 translocates to the nucleus and binds to the
from developing the detrimental characteristics of non–insu- classic sterol response element and/or to a palindrome CATG
lin-dependent diabetes. sequence. In the case of fatty acid synthase, SREBP-1 interacts
with a CATG palindrome that also functions as an insulin
PUFA Suppression of Lipogenesis: The Roles of response element (32). Overexpression of mature SREBP-1a
Sterol Regulatory Element Binding Protein-1, in liver is associated with high rates of fatty acid biosynthesis,
Nuclear Factor Y and Hepatic Nuclear Factor-4. Di- and ablation of the SREBP-1 gene results in low expression of
etary PUFA inhibit hepatic lipogenesis by suppressing the lipogenic genes (32,33). These observations led us to the
expression of a number of hepatic enzymes involved in glucose hypothesis that PUFA inhibit lipogenic gene transcription by
metabolism and fatty acid biosynthesis, including glucokinase, impairing the proteolytic release of SREBP-1c and/or by sup-
pyruvate kinase, glucose-6-phosphate dehydrogenase, citrate pressing SREBP-1c gene expression. Diets rich in 18:2(n-6) or
lyase, acetyl-CoA carboxylase, fatty acid synthase, stearoyl- 20:5 and 22:6(n-3) were found to reduce the hepatic nuclear
FATTY ACIDS AND GENE TRANSCRIPTION 1131
and precursor content of mature SREBP-1 by 65 and 90% and the mechanism by which PUFA regulate them are not well
by 60 and 75%, respectively (20). The decrease in SREBP-1 deﬁned. One hepatic protein that may be a PUFA target is
was accompanied by a comparable decrease in the transcrip- hepatic nuclear factor-4 (HNF-4). HNF-4 is a member of the
tion rate of hepatic fatty acid synthase (20). Unlike PUFA, steroid receptor superfamily. HNF-4 enhances the glucose/
saturated and monounsaturated fatty acids had no effect on the insulin induction of L-type pyruvate kinase transcription by
nuclear content or precursor content of SREBP-1 or on lipo- binding as a homodimer to a direct repeat-1 motif (4). Like
genic gene expression (20,29 –31,34). The PUFA-dependent PPAR , HNF-4 has a ligand binding domain that interacts
reduction in hepatic content of SREBP-1 may explain how with acyl-CoA esters, but unlike PPAR , fatty acyl-CoA
PUFA inhibit the transcription of several genes encoding binding to HNF-4 decreases its DNA-binding activity (37).
proteins involved in hepatic glucose metabolism and fatty acid This suggests that PUFA may exert part of its negative inﬂu-
biosynthesis, including glucokinase, acetyl-CoA carboxylase ence on gene transcription by reducing HNF-4 DNA-binding
and stearoyl-CoA desaturase (4). Interestingly, the inhibition activity. Linker scanner mutations through the carbohydrate
of lipogenic gene expression that reportedly occurs in adipose response region of the L-type pyruvate kinase promoter (i.e.,
tissue with the ingestion of ﬁsh oil does not involve an 183 to 97) did in fact reveal that the HNF-4 recognition
SREBP-1– dependent mechanism (30). elements were essential for PUFA suppression of the promoter
PUFA reduce the nuclear content of SREBP-1 via a two- (4). Recently, we found that sequences between 7242 and
phase mechanism. The ﬁrst phase is a rapid ( 60-min) inhibition 7150 of the fatty acid synthase gene were required for glu-
of the proteolytic release process (34). The second phase involves cose to induce fatty acid synthase gene transcription (38).
an adaptive ( 48-h) reduction in the hepatic content of Subsequent studies have demonstrated that the 7242 to
SREBP-1 mRNA that is subsequently followed by a reduction in 7150 sequence contains DNA recognition sites for HNF-4
the amount of precursor SREBP-1 protein (20,35). The mecha- and a novel carbohydrate response factor (38). Moreover,
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nism by which PUFA acutely inhibit the proteolytic processes is deleting this sequence eliminated 30 – 40% of the total PUFA
unknown. However, nuclear run-on assays suggested that PUFA suppression of the fatty acid synthase promoter (M. Teran-
reduce the hepatic content of SREBP-1 mRNA through post- Garcia and S. D. Clarke, unpublished data). Thus, PUFA may
transcriptional mechanisms (20,35). Using rat liver cells in pri- exert part of their suppressive effects on gene transcription by
mary culture, we determined that PUFA reduced the half-life of interfering with the glucose-mediated trans-activation pro-
SREBP-1c mRNA from 11 h to 5 h (35). The mechanism by cesses that in part involve reducing HNF-4 DNA-binding
which PUFA control the half-life of SREBP-1 is unknown but activity.
may require the synthesis of a rapidly turning over PUFA-depen-
dent protein (35). Summary. For nearly 40 y, PUFA have been known to
SREBP-1c by itself possesses weak trans-activating power, uniquely suppress lipid synthesis. PUFA, particularly (n-3),
but the binding of SREBP-1c to its recognition sequence accomplish this by coordinating an up-regulation of lipid ox-
enhances the upstream DNA binding of NF-Y and Sp1, which idation and a down-regulation of lipid synthesis. In other
in turn ampliﬁes the trans-activating activities of the three words, PUFA function as metabolic fuel repartitioners. The
transcription factors (32,36). NF-Y is a heterotrimeric nuclear outcome is an improvement in the symptoms of the metabolic
protein that reportedly plays a role in regulating chromatin syndrome and a reduced risk of heart disease. PUFA control
structure by way of its interaction with histone acetyl trans- these metabolic pathways by governing the DNA-binding
ferases (4). The binding sites for NF-Y are essential for fatty activity and nuclear abundance of select transcription factors
acid synthase (M. Teran-Garcia and S. D. Clarke, unpublished responsible for regulating the expression of genes encoding key
data) and S14 promoter activity (4). Mutations within the regulatory proteins of lipid and glucose metabolism. PUFA
Y-box region of 104 to 99 of the S14 gene eliminated increase the fatty acid oxidative capacity of tissues through
promoter activity by preventing NF-Y from interacting with their ability to function as ligand activators of PPAR and
upstream T3 ( 2800 to 2500) and carbohydrate response thereby induce the transcription of several genes encoding
( 1600 to 1400) regions (4). Similarly mutating the Y-box proteins afﬁliated with fatty acid oxidation.
motif between 90 and 80 of the rat fatty acid synthase gene PUFA suppress lipid synthesis by inhibiting transcription
eliminated 80% of the promoter activity, and mutating the factors that mediate the insulin and carbohydrate control of
adjacent Sp1 site ( 80) reduced promoter activity by 90% lipogenic and glycolytic genes. With respect to the insulin
(M. Teran-Garcia and S. D. Clarke, unpublished data). In response element, PUFA rapidly generate an intracellular sig-
contrast, eliminating the SREBP-1 site ( 67 to 53) reduced nal that immediately suppresses the proteolytic release of ma-
fatty acid synthase promoter activity by only 40%. More ture SREBP-1 from its membrane-anchored precursor and
important, only 35% of the PUFA inhibition of fatty acid simultaneously reduces the DNA-binding activities of NF-Y
synthase promoter activity was lost with the SREBP-1 muta- and Sp1. Within a matter of minutes after PUFA treatment,
tion. On the other hand, mutating the NF-Y site eliminated the nuclear content of SREBP-1c is greatly reduced. The drop
nearly 70% of the PUFA suppression of fatty acid synthase in nuclear content of SREBP-1c further contributes to the
promoter activity. Moreover, the near 90% inhibition in he- reduction in DNA binding of NF-Y and Sp1. Continued
patic fatty acid synthase gene transcription associated with the ingestion of PUFA subsequently lowers SREBP-1 mRNA lev-
ingestion of a diet rich in ﬁsh oil was accompanied by a els by accelerating transcript decay, which in turn results in a
50 – 60% reduction in DNA-binding afﬁnity for NF-Y and Sp1 lower hepatic content of precursor, endoplasmic reticulum–
(M. Teran-Garcia and S. D. Clarke, unpublished data). anchored SREBP-1. With regard to the carbohydrate response
The insulin response region and its associated transcription element, PUFA may also mediate reductions in the DNA-
factors (i.e., SREBP-1, NF-Y and Sp1) are not the only nuclear binding activity of pivotal transcription factors (e.g., HNF-4),
factors regulated by PUFA. Transfection-reporter analyses in- but the nature of the affected transcription factors remains to
dicate that PUFA exert a negative inﬂuence on the carbohy- be unequivocally established. Without question, the missing
drate response element of the L-type pyruvate kinase (4) and ﬁnal chapter in the entire PUFA-regulatory story is the nature
fatty acid synthase genes (M. Teran-Garcia and S. D. Clarke, of the intracellular signal responsible for regulating the various
unpublished data). The nature of the transcription factors and affected transcription factors.
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