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					                            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
                                                                                             PUFA (10,11).
                                                                                                 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
    1
      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
    2
      Manuscript received 9 January 2001.
    3
      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: stevedclarke@mail.utexas.edu              receptor superfamily, and like other steroid receptors, it possesses
    4
      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.


                                                                                      1129
1130                                                                 CLARKE


                                                                          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.
1132                                                                                  CLARKE


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