Download I. Molecular mechanism for polyunsaturated fatty acid regulation of

Am J Physiol Gastrointest Liver Physiol
281: G865–G869, 2001.
themes
Nonalcoholic Steatosis and Steatohepatitis. I. Molecular
mechanism for polyunsaturated fatty acid regulation
of gene transcription
Clarke, Steven D. Nonalcoholic Steatosis and Steatohepatitis. I. Molecular mechanism for polyunsaturated fatty acid
regulation of gene transcription. Am J Physiol Gastrointest
Liver Physiol 281: G865–G869, 2001.—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
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
DIETARY
Address for reprint requests and other correspondence: S. D.
Clarke, 115 Gearing Bldg., Univ. of Texas, Austin, TX 78712 (E-mail:
[email protected]).
http://www.ajpgi.org
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-forcarbon 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.
0193-1857/01 $5.00 Copyright © 2001 the American Physiological Society
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STEVEN D. CLARKE
Graduate Program of Nutrition and Institute of Cell and Molecular Biology,
University of Texas at Austin, Austin, Texas 78712
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FATTY ACIDS AND GENE TRANSCRIPTION
Fig. 1. Nuclear mechanism for polyunsaturated
fatty acid (PUFA) regulation of gene expression.
FA, fatty acids; NF-Y nuclear factor Y; PPAR,
peroxisome proliferator-activated receptor; PPRE,
peroxisome proliferator-activated receptor response element; Sp1, stimulatory protein-1;
SREBP-1, sterol regulatory element binding protein-1; TG, triglycerides; VLDL, very low-density
lipoprotein.
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 PUFAmediated 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 lipidactivated 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 palmitoyltransAJP-Gastrointest Liver Physiol • VOL
ferase, hepatic and skeletal muscle peroxisomal acylCoA 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).
PUFA SUPPRESSION OF LIPOGENESIS: ROLE OF
STEROL REGULATORY ELEMENT BINDING PROTEIN-1,
NUCLEAR FACTOR Y, AND HEPATIC
NUCLEAR FACTOR-4
Dietary PUFA inhibit hepatic lipogenesis by suppressing the expression of a number of hepatic en281 • OCTOBER 2001 •
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PUFA INDUCTION OF LIPID OXIDATION: ROLE
OF PEROXISOME PROLIFERATOR-ACTIVATED
RECEPTOR-␣
FATTY ACIDS AND GENE TRANSCRIPTION
AJP-Gastrointest Liver Physiol • VOL
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 PUFAdependent 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
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zymes involved in glucose metabolism and fatty acid
biosynthesis including glucokinase, pyruvate kinase,
glucose-6-phosphate dehydrogenase, citrate lyase,
acetyl-CoA carboxylase, fatty acid synthase, stearoylCoA 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).
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AJP-Gastrointest Liver Physiol • VOL
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.
SUMMARY
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 reticulumanchored 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.
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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