Graduate Program of Nutrition and Institute of Cell and Molecular Biology, University of Texas at Austin, Austin, Texas 78712
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ABSTRACT |
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This review addresses the hypothesis that
polyunsaturated fatty acids (PUFA), particularly those of the n-3
family, play pivotal roles as "fuel partitioners" in that they
direct fatty acids away from triglyceride storage and toward oxidation
and they enhance glucose flux to glycogen. In doing this, PUFA may
reduce the risk of enhanced cellular apoptosis associated with
excessive cellular lipid accumulation. PUFA exert their beneficial
effects by upregulating the expression of genes encoding proteins
involved in fatty acid oxidation while simultaneously downregulating
genes encoding proteins of lipid synthesis. PUFA govern oxidative gene
expression by activating the transcription factor peroxisome
proliferator-activated receptor-. PUFA suppress lipogenic gene
expression by reducing the nuclear abundance and DNA binding affinity
of transcription factors responsible for imparting insulin and
carbohydrate control to lipogenic and glycolytic genes. In particular,
PUFA suppress the nuclear abundance and expression of sterol regulatory
element binding protein-1 and reduce the DNA binding activities of
nuclear factor Y, stimulatory protein 1, and possibly hepatic nuclear
factor-4. Collectively, the studies discussed suggest that the fuel
"repartitioning" and gene expression actions of PUFA should be
considered among the criteria used in defining the dietary needs of n-6
and n-3 fatty acids and in establishing the dietary ratio of n-6 to n-3
fatty acids needed for optimum health benefit.
sterol regulatory element binding protein; fatty livers; nuclear factor Y; transcription
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INTRODUCTION |
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DIETARY n-6 and n-3
polyunsaturated fatty acids (PUFA) reduce triglyceride accumulation in
skeletal muscle and potentially in cardiomyocytes and -cells
(2, 12, 25). Lower tissue lipids are associated with
improvements in glucose metabolism and may reduce the enhanced
rate of apoptosis associated with cellular lipid
accumulation (3, 12, 25). PUFA elicit their effects by
coordinately suppressing lipid synthesis in the liver and upregulating
fatty acid oxidation in liver and skeletal muscle (3, 6, 7, 11,
18, 20), and on a carbon-for-carbon basis n-3 fatty acids are
more potent than n-6 fatty acids (3, 11, 22). Moreover,
the lipid synthesis pathway is more sensitive to PUFA regulation than
the lipid oxidation pathway, and both pathways are more sensitive to
PUFA feedback in the liver than in the skeletal muscle (3, 11,
22). The "repartitioning" activity of PUFA has been observed
in humans as well as various animal models (2, 6, 18), but
the amount of n-6 and n-3 fatty acids and the best n-6 to n-3 ratio
required for optimum metabolic benefit are unknown. However, as little
as 2-5 g of 18:3(n-3) or 20:5 and 22:6(n-3) lower blood
triglycerides and reduce the risk of fatal ischemic heart
disease (reviewed in Ref. 3).
The fuel repartitioning effect of PUFA requires that 18:2(n-6) and
18:3(n-3) undergo -6 desaturation (16).
Interestingly, loss of
-6 desaturase activity is associated with
liver failure in humans (Blake WL and Clarke SD, unpublished
data). The recent cloning of the human
-6 and -5 desaturase
genes will allow us to ascertain whether low
-6/
-5 desaturation
plays a causative role in the development of fatty liver syndrome in
humans (4, 5).
Some of the beneficial effects of PUFA are caused by changes in
membrane fatty acid composition and subsequent alterations in hormonal
signaling. However, fatty acids themselves exert a direct,
membrane-independent influence on molecular events that govern gene
expression (Fig. 1). We believe that the
regulation of gene expression by dietary fats has the greatest impact
on the development of disorders in lipid and glucose metabolism. More
importantly, determination of the cellular and molecular mechanisms
regulated by PUFA may identify novel sites for pharmacological intervention.
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PUFA INDUCTION OF LIPID OXIDATION: ROLE OF PEROXISOME
PROLIFERATOR-ACTIVATED RECEPTOR-![]() |
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One of the first steps in the PUFA-dependent repartitioning of metabolic fuels involves an immediate reduction in the production of hepatic malonyl-CoA (3). Malonyl-CoA is a negative metabolite effector of carnitine palmitoyltransferase (24). Consequently, a PUFA-mediated decrease in hepatic malonyl-CoA favors fatty acid entry into the mitochondria and peroxisomes and leads to enhanced fatty acid oxidation (24). Whether PUFA suppress malonyl-CoA levels in skeletal muscle and heart remains to be determined, but such a mechanism would be consistent with the higher rates of fatty acid oxidation observed in humans and animals fed diets rich in PUFA (6, 18).
The reduction in hepatic malonyl-CoA is paralleled by a PUFA-dependent
induction of genes encoding proteins involved in fatty acid oxidation
and ketogenesis (3, 7, 11). These changes in 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 consistent with the idea that
PUFA directly (e.g., ligand binding) regulate the activity or abundance
of a nuclear transcription factor. In 1990, peroxisome
proliferator-activated receptor (PPAR)-, a novel lipid-activated
transcription factor, was cloned (10). PPAR-
is a
member of the steroid receptor superfamily, and like other steroid
receptors it possesses a DNA binding domain and a ligand binding domain
(10, 13-15). Interaction of PPAR-
with its DNA recognition site is markedly enhanced by ligands such as the
hypotriglyceridemic fibrate drugs, conjugated linoleic acid, and PUFA
(10, 13-15, 20). In general, PPAR-
activation
leads to the induction of several genes encoding proteins involved in
lipid transport, oxidation, and thermogenesis including hepatic
carnitine palmitoyltransferase, hepatic and skeletal muscle peroxisomal
acyl-CoA oxidase, and muscle uncoupling protein-3 (1, 3, 13,
20). The n-3 PUFA are more potent than the n-6 PUFA as in vivo
activators of PPAR-
(13-15), but neither family of
PUFA is a particularly strong PPAR-
activator. However, PUFA
metabolites such as eicosanoids or oxidized fatty acids have one to two
orders of magnitude greater affinity for PPAR-
and are consequently
far more potent transcriptional activators of PPAR-
-dependent genes
(15).
The importance of PPAR- to overall glucose and fatty acid
homeostasis has been clearly demonstrated in PPAR-
knockout mice (4, 22). Because PPAR-
/
mice lack the
ability to increase rates of fatty acid oxidation during periods of
food deprivation, they develop characteristics of adult-onset diabetes
including fatty liver, elevated blood triglycerides, and hyperglycemia
(13). The essentiality of PPAR-
to lipid oxidation was
further underscored when hyperglycemia was found to suppress PPAR-
expression, induce PPAR-
expression, increase
-cell and
cardiomyocyte lipids, and accelerate cell death (25). Such
"lipotoxicity" may be a contributing factor to the complications of
cellular lipid overload (12, 25). Clearly, PPAR-
is
emerging as a pivotal player in both fatty acid and glucose metabolism.
More importantly, its regulation by PUFA, particularly n-3 PUFA and
possibly conjugated linoleic acid, may offer an explanation for the
reported benefits of these fatty acids in protecting individuals from
developing the detrimental characteristics of non-insulin-dependent
diabetes (reviewed in Ref. 3).
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PUFA SUPPRESSION OF LIPOGENESIS: ROLE OF STEROL REGULATORY ELEMENT BINDING PROTEIN-1, NUCLEAR FACTOR Y, AND HEPATIC NUCLEAR FACTOR-4 |
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Dietary PUFA inhibit hepatic lipogenesis by suppressing the
expression of a number of hepatic enzymes involved in glucose metabolism and fatty acid biosynthesis including glucokinase, pyruvate
kinase, glucose-6-phosphate dehydrogenase, citrate lyase, acetyl-CoA
carboxylase, fatty acid synthase, stearoyl-CoA desaturase, and the
-6 and
-5 desaturases (2-5, 8, 11, 17, 22, 23).
The discovery of PPAR-
led quickly to the idea that PPAR-
was a
"master switch" transcription factor that is targeted by PUFA to
coordinately suppress genes encoding proteins of lipid synthesis and
induce genes encoding proteins of lipid oxidation. This attractive
hypothesis was strengthened by reports that potent pharmacological
activators of PPAR-
modestly reduced lipogenic gene transcription
(11, 20). However, PPAR-
does not appear to interact
with PUFA response sequences of lipogenic genes (3, 11,
22). Moreover, PUFA continue to suppress the transcription of
hepatic lipogenic genes in PPAR-
/
mice
(11). Thus the inhibition of lipogenic gene transcription associated with PPAR-
activation is indirect and may simply reflect the PPAR-
-dependent induction of the
-6 desaturase pathway (Ref. 16; Tang Z, Cho HP, Nakamura MT, and Clarke SD,
unpublished data).
PUFA response sequences have been well characterized in only three
genes: fatty acid synthase, S14, and L-type pyruvate kinase (3,
11, 22). The rat fatty acid synthase gene contains two
independent PUFA regulatory sequences that are located between 118
and
43 and between
7250 and
7035 (Teran-Garcia M and Clarke SD,
unpublished data). Approximately 65% and 35% of the PUFA control can
be 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 the PUFA
response region of the S14 gene (
220 to
80), whereas the distal
PUFA response region of the fatty acid synthase has similarities to the
L-type pyruvate kinase PUFA response region (
160 to
97)
(11).
The proximal PUFA response region of the fatty acid synthase gene imparts insulin responsiveness to the gene and contains DNA binding sites for sterol regulatory element binding protein (SREBP)-1, upstream stimulatory factor (USF), stimulatory protein 1 (Sp1), and nuclear factor Y (NF-Y) (21, 22). The nuclear abundance of USF is unaffected by dietary PUFA (22). In contrast, PUFA rapidly reduce the nuclear content of hepatic SREBP-1, and this is associated with a decrease in the rate of fatty acid synthase and S14 gene transcription (7, 8, 17, 22, 23). SREBPs are a family of transcription factors (i.e., SREBP-1a, -1c, and -2) that were first isolated as a result of their properties for binding to the sterol regulatory element (2, 17). SREBP-2 is a regulator of genes encoding proteins involved in cholesterol metabolism (2). SREBP-1 exists in two forms, 1a and 1c. SREBP-1a is the dominant form in cell lines and is a regulator of genes encoding proteins involved in both lipogenesis and cholesterolgenesis. SREBP-1c constitutes 90% of the SREBP-1 found in vivo and is a determinant of lipogenic gene transcription (2, 17, 23).
SREBP-1 is synthesized as a 125-kDa precursor protein that is anchored
in the endoplasmic reticulum membrane (2, 17). Proteolytic
release of the 68-kDa mature SREBP-1 occurs in the golgi system, and
movement of SREBP-1 from the endoplasmic reticulum to the golgi
requires the trafficking protein SREBP cleavage-activating protein
(SCAP) (2, 8). Once released, mature SREBP-1 translocates to the nucleus and binds to the classic sterol response element and/or
to a palindrome CATG sequence. In the case of fatty acid synthase,
SREBP-1 interacts with a CATG palindrome that also functions as an
insulin response element (2). Overexpression of mature SREBP-1a in liver is associated with high rates of fatty acid biosynthesis and the development of fatty liver (2, 17). In contrast, the ablation of the SREBP-1 gene results in low expression of lipogenic genes (2, 7, 17). These observations led us
to hypothesize that PUFA inhibit lipogenic gene transcription by
impairing the proteolytic release of SREBP-1c and/or by suppressing SREBP-1c gene expression (22, 23). Diets rich in 18:2(n-6) or 20:5 and 22:6(n-3) were found to reduce the hepatic nuclear and
precursor content of mature SREBP-1 65% and 90% and 60% and 75%,
respectively (22). The decrease in SREBP-1c was
accompanied by a comparable decrease in the transcription rate of
hepatic fatty acid synthase (22). Unlike PUFA, saturated
and monounsaturated fats had no effect on the nuclear content or
precursor content of SREBP-1 or on lipogenic gene expression (8,
22, 23). The PUFA-dependent reduction in hepatic content of
SREBP-1 may explain how PUFA inhibit the transcription of several genes
encoding proteins involved in hepatic glucose metabolism and fatty acid biosynthesis including glucokinase, acetyl-CoA carboxylase,
stearoyl-CoA desaturase, and the -6 and
-5 desaturases (4,
5, 7, 11, 22). Interestingly, the inhibition of lipogenic gene
expression that reportedly occurs in adipose tissue with the ingestion
of fish oil does not involve an SREBP-1-dependent mechanism (30).
PUFA reduce the nuclear content of SREBP-1 by a two-phase mechanism. The first phase is a rapid (<60 min) inhibition of the proteolytic release process (8, 23). The second phase involves an adaptive (~48 h) reduction in the hepatic content of SREBP-1 mRNA that is followed by a reduction in the amount of precursor SREBP-1 protein (22, 23). The mechanism by which PUFA acutely inhibit the proteolytic processes is unknown. However, nuclear run-on assays suggested that PUFA reduce the hepatic content of SREBP-1 mRNA by posttranscriptional mechanisms (22, 23). Using rat liver cells in primary culture, we determined that PUFA reduces the half-life of SREBP-1c mRNA from 11 h to <5 h (23). The mechanism by which PUFA control the half-life of SREBP-1 is unknown, but it may require the synthesis of a rapidly turning over PUFA-dependent protein (23).
SREBP-1c by itself possesses weak trans-activating power,
but the binding of SREBP-1c to its recognition sequence enhances the
upstream DNA binding of NF-Y and Sp1, which in turn amplifies the
trans-activating activities of the three transcription
factors (17). NF-Y is a heterotrimeric nuclear protein
that reportedly plays a role in regulating chromatin structure by way
of its interaction with histone acetyl transferases. The binding sites
for NF-Y are essential for fatty acid synthase (21) and
S14 promoter activity (11). Mutations within the Y box
region of 104 to
99 of the S14 gene eliminated promoter activity by
preventing NF-Y from interacting with upstream T3 (
2800 to
2500)
and carbohydrate response (
1600 to
1400) regions (11).
Similarly mutating the Y box motif between
90 and
80 of the rat
fatty acid synthase gene eliminated 80% of the promoter activity, and
mutating the adjacent Sp1 site (
80) reduced promoter activity by
>90% (Teran-Garcia M and Clarke SD, unpublished data). In contrast,
eliminating the SREBP-1 site (
67 to
53) reduced fatty acid synthase
promoter activity by only 40%. More importantly, only 35% of the PUFA
inhibition of fatty acid synthase promoter activity was lost with the
SREBP-1 site mutation. On the other hand, mutating the NF-Y site
eliminated nearly 70% of the PUFA suppression of fatty acid synthase
promoter activity. Moreover, the near 90% inhibition in hepatic fatty
acid synthase gene transcription associated with the ingestion of a diet rich in fish oil was accompanied by a 50-60% reduction in DNA binding affinity for NF-Y and Sp1 (Teran-Garcia M and Clarke SD,
unpublished data).
The insulin response region and its associated transcription factors
(i.e., SREBP-1, NF-Y, and Sp1) are not the only nuclear factors
regulated by PUFA. Transfection-reporter analyses indicate that PUFA
exert a negative influence on the carbohydrate response element of the
L-type pyruvate kinase (4) and fatty acid synthase genes
(Teran-Garcia M and Clarke SD, unpublished data). The nature of the
transcription factors and the mechanism by which PUFA regulate them are
not well defined. One hepatic protein that may be a PUFA target is
hepatic nuclear factor (HNF)-4. HNF-4 is a member of the steroid
receptor superfamily. HNF-4 enhances the glucose/insulin induction of
L-type pyruvate kinase transcription by binding as a homodimer to a
direct repeat-1 motif (9). Like PPAR-, HNF-4 has a
ligand binding domain that interacts with acyl-CoA esters, but unlike
PPAR-
, fatty acyl-CoA binding to HNF-4 decreases its DNA binding
activity (9). This suggests that PUFA may exert part of
its negative influence on gene transcription by reducing HNF-4 DNA
binding activity. Linker scanner mutations through the carbohydrate
response region of the L-type pyruvate kinase promoter (i.e.,
183 to
97) did in fact reveal that the HNF-4 recognition elements were
essential for PUFA suppression of the promoter (11). Recently, we found that sequences between
7242 and
7150 of the fatty acid synthase gene were required for glucose to induce fatty acid
synthase gene transcription (19). Subsequent studies have demonstrated that the
7242 to
7150 region contains DNA recognition sites for HNF-4 and a novel carbohydrate response factor
(19). Moreover, deleting this sequence eliminated
30-40% of the total PUFA suppression of the fatty acid synthase
promoter (Teran-Garcia M and Clarke SD, unpublished data). Thus PUFA
may exert part of their suppressive effects on gene transcription by
interfering with the glucose-mediated trans-activation
processes that in part involve reduction of HNF-4 DNA binding activity.
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SUMMARY |
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PUFA have been known for nearly 40 years to uniquely suppress
lipid synthesis. PUFA, particularly n-3, accomplish this by coordinating an upregulation of lipid oxidation and a downregulation of
lipid synthesis. In other words, PUFA function as metabolic fuel
"repartitioners." Such fuel repartitioning may protect cells against the accelerated rates of apoptosis reportedly observed with excessive triglyceride accumulation (12, 25).
PUFA exert their effects on metabolic pathways by governing the DNA
binding activity and nuclear abundance of select transcription factors responsible for regulating the expression of genes encoding key regulatory proteins of lipid and glucose metabolism. With respect to
their role in fatty acid oxidation, PUFA increase the fatty acid
oxidative capacity of tissues through their ability to function as
ligand activators of PPAR- and thereby induce the transcription of
several genes encoding proteins affiliated with fatty acid oxidation.
On the other hand, PUFA suppress lipid synthesis by inhibiting
transcription factors that mediate the insulin and carbohydrate control
of lipogenic and glycolytic genes. In this regard, PUFA rapidly
generate an intracellular signal that immediately suppresses the
proteolytic release of mature SREBP-1 from its membrane-anchored
precursor and simultaneously reduces the DNA binding activities of NF-Y
and Sp1. Within a matter of minutes after PUFA treatment, the nuclear
content of SREBP-1c is greatly reduced. The drop in nuclear content of
SREBP-1c further contributes to the reduction in DNA binding of NF-Y
and Sp1. Continued ingestion of PUFA subsequently lowers SREBP-1 mRNA
levels by accelerating transcript decay, which in turn results in a
lower hepatic content of precursor endoplasmic reticulum-anchored
SREBP-1. With regard to the carbohydrate response element, PUFA may
also mediate reductions in the DNA binding activity of pivotal
transcription factors (e.g., HNF-4), but the nature of the affected
transcription factors remains to be unequivocally established. Without
question, the missing final chapter in the entire PUFA-regulatory story
is the nature of the intracellular signal responsible for regulating
the various affected transcription factors.
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ACKNOWLEDGEMENTS |
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This work was supported by grants from the National Institutes of Health (DK-53872 and HD-37133) and by the sponsors of the M. M. Love Chair of Nutritional, Cellular, and Molecular Sciences, University of Texas at Austin.
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FOOTNOTES |
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Address for reprint requests and other correspondence: S. D. Clarke, 115 Gearing Bldg., Univ. of Texas, Austin, TX 78712 (E-mail: stevedclarke{at}mail.utexas.edu).
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