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Department of Nutritional Sciences, University of California, Berkeley, CA 94720
3To whom correspondence should be addressed.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONHormonal and nutritional...Insulin response sequence of...Signal transduction pathway for...ProspectiveREFERENCES |
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KEY WORDS: • fatty acid synthase • glycerol-3 phosphate acyltransferase • insulin • USF • transcription
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONHormonal and nutritional...Insulin response sequence of...Signal transduction pathway for...ProspectiveREFERENCES |
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). We review here our results on
dietary and hormonal regulation of fatty acid synthase
(FAS)4
and mitochondrial glycerol-3-phosphate acyltransferase (GPAT) gene
transcription, focusing on the regulation of the FAS promoter by
insulin. |
Hormonal and nutritional regulation of the FAS and mitochondrial GPAT gene transcription |
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TOPABSTRACTINTRODUCTIONHormonal and nutritional...Insulin response sequence of...Signal transduction pathway for...ProspectiveREFERENCES |
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By the action of its seven active sites, FAS catalyzes all of the
reaction steps in the conversion of acetyl-CoA and malonyl-CoA
to palmitate. Mitochondrial GPAT catalyzes the first committed step in
glycerophospholipid biosynthesis by catalyzing acylation of
glycerol-3-phosphate using fatty acyl-CoA to generate
1-acylglycerol-3-phosphate (lysophosphatidic acid). Lysophosphatidic
acid is further acylated to form triacylglycerol for storage. FAS
activity is not known to be regulated by allosteric effectors or
covalent modification. However, FAS concentration is exquisitely
sensitive to nutritional, hormonal and developmental status; the
concentration or activity of FAS in lipogenic tissues, i.e., liver and
adipose tissue, changes dramatically when animals are subjected to
different nutritional and hormonal manipulations. For example, the rate
of FAS synthesis declines when rats are deprived of food for 1–2 d,
whereas refeeding a high carbohydrate, fat-free diet increases
synthesis of FAS (Volpe and Vagelos 1974
). FAS provided
a good model system with which to study potential transcriptional
regulation. We identified the murine FAS cDNA sequence by differential
screening, exploiting the fact that FAS is induced by fasting/refeeding
(Paulauskis and Sul 1988
). We also cloned the cDNA for
mitochondrial GPAT, whose regulation had not been studied previously
(Yet et al. 1993
and 1995
). Regulation of the FAS and
mitochondrial GPAT genes by hormones and nutrients, with an emphasis on
transcriptional activation by insulin, were studied in our laboratory.
Both FAS and mitochondrial GPAT mRNAs are present at high levels in
lipogenic rodent tissues, liver and adipose tissue (Paulauskis and Sul 1989
, Shin et al. 1991
). mRNAs for FAS
and mitochondrial GPAT were not detectable in the liver of normal
fasted mice, and refeeding a high carbohydrate diet increased the
levels by two orders of magnitude. However, in
streptozotocin-diabetic mice, the mRNA levels for these enzymes did
not increase after refeeding, indicating that insulin is required for
induction of these mRNAs by fasting/refeeding. Dibutyryl cAMP,
administered at the time of refeeding, inhibited the induction of the
two mRNAs by 90%. These data indicate that the barely detectable
levels of these mRNAs during fasting may be due in part to the
increased plasma glucagon that increases intracellular cAMP. The effect
of insulin can be demonstrated further by administering insulin to
streptozotocin-diabetic mice. The induction of FAS and GPAT mRNAs
by insulin was rapid and marked. Transcription run-on analyses were
carried out in isolated liver nuclei (Fig. 1
). The transcription of the FAS and mitochondrial GPAT genes increased
when previously fasted mice were refed a high carbohydrate diet. The
maximal increase (39-fold) for FAS was attained at 6 h after
refeeding and was maintained up to 16 h, whereas increase in
transcription of the mitochondrial GPAT gene was substantially slower,
i.e., 2.5-fold at 6 h, 7-fold at 9 h and reached 22-fold
after 16 h of refeeding. However, there was no detectable
transcription of FAS and mitochondrial GPAT genes in fasted or
fasted-refed streptozotocin-diabetic mice, indicating that insulin
is required for transcriptional induction by fasting/refeeding.
Administration of cAMP at the start of feeding in normal mice prevented
an increase in the transcription of these genes by feeding.
Furthermore, there was a rapid and marked increase in the transcription
rates of the FAS and GPAT genes when insulin was given to diabetic
mice; the rates increased approximately 4-fold after 0.5 h with a
maximal increase of seven- to eightfold at 2 h (Paulauskis and Sul 1989
, Shin et al. 1991
). The results
demonstrate that these genes are highly regulated at the
transcriptional level by nutritional and hormonal stimuli. The
molecular mechanisms underlying transcriptional regulation of these
genes must be elucidated.
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Insulin response sequence of the FAS gene and upstream stimulatory factor (USF) function |
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TOPABSTRACTINTRODUCTIONHormonal and nutritional...Insulin response sequence of...Signal transduction pathway for...ProspectiveREFERENCES |
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). The CAT reporter driven by the
FAS promoter was expressed strongly only in tissues such as liver and
white adipose tissue, which normally contain high FAS mRNA levels
(Fig. 2
). Moreover, CAT activity was low in fasted transgenic mice; it was
increased in liver and white adipose tissue but not in other tissues of
fasted animals refed a high carbohydrate, fat-free diet.
Interestingly, administration of dibutyryl cAMP at the start of
refeeding prevented an increase in CAT activity in liver but not in
adipose tissue. Streptozotocin-diabetic transgenic mice showed very
low CAT activity, but insulin administration caused an increase in CAT
expression in liver and adipose tissue. Administration of
glucocorticoids increased CAT activity in all tissues examined, i.e.,
liver, adipose tissue, lung, heart and spleen. We examined effects of
dietary polyunsaturated fatty acids (PUFA) on FAS expression in
transgenic mice. Although the molecular basis is not clear, PUFA can
suppress the expression of several genes involved in hepatic lipid
metabolism, including FAS (Muto and Gibson 1970
). PUFA
repressed FAS gene transcription in liver (Armstrong et al. 1991
). On the other hand, PUFA were reported to have only a
slightly suppressive effect on FAS mRNA levels in adipose tissue in
which both saturated and unsaturated fatty acids depress de novo fatty
acid synthesis. In our studies, FAS mRNA levels were suppressed
markedly in both liver and adipose tissue in mice fed menhaden oil
compared with those fed triolein. CAT activity driven by the FAS
promoter in these tissues from mice fed menhaden oil was only 2-fold
lower than that of the mice fed triolein. A possibility is that FAS may
be regulated by PUFA at the level of mRNA stability as well as at the
transcriptional level. Regulation of the FAS mRNA levels by message
stabilization has been observed; we previously reported that the
dramatic increase in FAS mRNA levels during 3T3-L1 adipocyte
differentiation occurs both by an increase in FAS gene transcription
and by stabilization of FAS mRNA (Moustaid and Sul 1991
). It has also been reported that an increase in FAS mRNA
levels in hepG2 cells maintained in a medium containing a high level of
glucose was due to the stabilization of FAS mRNA (Semenkovich et al. 1993
). Overall, the results from transgenic mice studies
demonstrate that the 2.1-kb 5'-flanking sequence of the FAS gene is
sufficient not only for tissue-specific expression but also for
transcriptional regulation by various hormonal/nutritional stimuli.
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, Sul 1989
). Many of the genes coding for
enzymes involved in fatty acid and lipid metabolism, including FAS and
mitochondrial GPAT, are induced. In addition, the differentiated
adipocytes become responsive to lipolytic and lipogenic hormones,
including insulin. The insulin receptor number in these cells increases
during adipose conversion. When fully differentiated adipocytes were
treated with insulin for 13 h, levels for FAS and mitochondrial
GPAT mRNAs increased 3-fold, whereas cAMP treatment caused a decrease
in mRNA levels (Paulauskis and Sul 1988
). These data
indicate that regulation of the FAS and mGPAT genes in 3T3-L1
adipocytes mimics in vivo regulation; thus, differentiated 3T3-L1
adipocytes provide a good in vitro model system for studying lipogenic
gene regulation.
To identify sequences responsible for insulin regulation of the FAS
gene, we prepared fusion constructs containing 5' deletions of the FAS
promoter linked to the CAT reporter gene and transiently transfected
into fully differentiated 3T3-L1 adipocytes. Plasmids containing 5'
deletions at -2100, -1400, -1009 and -332 to +67 relative to the
transcription start site exhibited a 2- to 3-fold increase in CAT
activity when the cells were treated with 10 nmol/L of insulin
(Moustaid et al. 1993
). Similarly, the stable
transfectants of all four constructs showed a 3-fold increase in CAT
activity when the adipocytes were treated with insulin. A similar
increase in CAT activity was also observed when H4IIE hepatoma cells,
transiently transfected with these constructs, were treated with
insulin. Thus, we concluded that the insulin response element was
located in the first 332 bp of the FAS promoter. We also observed that
glucose was required for the insulin effect; when glucose in the medium
was replaced with lactose, no insulin effect on CAT activity was
observed. This observation is in agreement with the reported effect of
glucose on insulin-stimulated FAS activity in primary hepatocytes
(Giffhorn-Katz and Katz 1986
) and suggests that an
increase in glycolysis is likely necessary for insulin regulation of
FAS expression.
To define minimal sequences required for insulin regulation within the
first 322 bp of the FAS promoter, we generated constructs containing
serial 5' deletions starting at -318 and extending through position
+67 of the FAS gene ligated to the luciferase reporter gene
(Moustaid et al. 1994
). Insulin increased luciferase
activity 2- to 3-fold in 3T3-L1 adipocytes transfected with constructs
containing progressive deletions from -318 to -67. Although not
dramatic, the observed stimulation of FAS promoter activity by insulin
was consistent and dose dependent: maximal activity was observed at 10
nmol/L insulin and half-maximal activity below 1 nmol/L insulin,
indicating that the insulin effect on the FAS promoter is at the
physiologic concentration of insulin. However, insulin had no effect
when reporter constructs containing FAS promoter sequences spanning
from -25 or -19 to +67 were transfected into adipocytes. These
results indicate that the insulin response sequence of the FAS gene is
located in the region from -67 to -25. DNase I footprinting analysis
using liver nuclear extracts revealed a protected region spanning -71
to -50 of the FAS promoter in addition to a region near the putative
TATA box. Gel mobility shift assays with the sequence from -71 to -50
used as a probe revealed nuclear factor(s) from mouse liver and 3T3-L1
adipocytes that specifically complexed with this sequence. Mutational
analysis of -71 to -50 showed that sequences between -68 and -60
with a core E-box were essential for recognition and interaction
with trans-acting factors. Moreover, when three tandem
repeats of the sequence spanning -68 to -52 were linked to the SV40
promoter and used for transfection, luciferase activity increased
3.6-fold in response to insulin. Thus, we have identified a novel
cis-acting DNA sequence, responsible for insulin regulation
of the FAS gene, that interacts with nuclear proteins from liver and
adipocytes. The minimal sequence for insulin regulation that we defined
contains an E-box DNA-binding motif 5'-CATGTG-3'. USF, a basic
helix-loop-helix leucine zipper family of the transcription factors
that bind to an E-box, has been implicated in the transcriptional
activation of L-pyruvate kinase by glucose when the level of
insulin is also high (Lefrancois-Martinez et al. 1995
,
Shih et al. 1995
). We therefore tested the possible
involvement of USF in the insulin regulation of the FAS promoter
(Wang and Sul 1995
). By gel shift competition assays, we
showed that L-pyruvate kinase glucose response sequences
effectively disrupted the IRS-protein complex formation. Moreover,
we were able to supershift the FAS IRS-protein complex using
antibodies against USF1or USF2 that are known to heterodimerize and
bring about transcriptional activation (Fig. 3A
). Thus, USF1 and USF2 are both present in the FAS-IRS–protein complex.
To further support the involvement of USF as a protein-binding
component to the FAS-IRS, we performed UV-crosslinking
experiments. A major crosslinked band of 49 kDa was observed:
subtraction of ~6 kDa for the IRS probe resulted in a 43-kDa protein,
consistent with the size of USF1 (43 kDa) and USF2 (44 kDa). Moreover,
cotransfection of USF1 and USF2 expression vectors with the FAS
promoter-luciferase reporter constructs increased
insulin-stimulated FAS promoter activity (Wang and Sul 1997
). In addition, dominant negative USF1 and USF2 mutants
lacking the DNA binding domain inhibited insulin stimulation of the FAS
promoter (Fig. 3
B). These studies clearly demonstrate that
USF binding to the E-box at -65 is required for insulin regulation
of the FAS gene. Recently, Vaulont and co-workers reported that in
USF1 and USF2 knockout mice fed a carbohydrate diet, FAS induction was
severely impaired, demonstrating that USF1 and USF2 are required in the
induction of the FAS gene in vivo by glucose/insulin (Casado et al. 1999
). Osborne and co-workers reported the presence of
two tandem SREBP-1 binding sites overlapping the -65 E-box, each
occupying half of the E-box (Magana and Osborne 1996
). SREBP binding to these sites was reported to be
responsible for sterol regulation of FAS gene transcription. SREBP also
belong to the basic helix-loop-helix leucine zipper family of
transcription factors can bind to E-box and SRE sites.
Site-directed mutagenesis of the -65 to -60 E-box surrounding
sequences with the overlapped tandem copies of SREBP binding sites
prevented SREBP binding but had no effect on insulin regulation of FAS
promoter activity (Wang and Sul 1997
). Recently,
Spiegelman and co-workers reported that SREBP-1c, an isoform of
SREBP-1, is induced by refeeding a carbohydrate-enriched diet and
that mutated SREBP that can bind only to the E-box can
transactivate the FAS promoter by binding to the -65 E-box
(Kim et al. 1998
). Goldstein and Brown demonstrated that
overexpression of the truncated active form of SREBP-1 in liver causes
a large accumulation of triacylglycerol and the induction of lipogenic
genes including FAS and mitochondrial GPAT (Shimano et al. 1996
). SREBP-1 probably plays an important role in lipogenic
gene induction during refeeding. Further studies are required to
elucidate SREBP function in the control of FAS promoter.
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Signal transduction pathway for insulin regulation of the FAS promoter |
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TOPABSTRACTINTRODUCTIONHormonal and nutritional...Insulin response sequence of...Signal transduction pathway for...ProspectiveREFERENCES |
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) (Wang and Sul 1998
). Although inhibition of MAP kinase and S6
kinase activity by PD98059 and rapamycin, respectively, had little
effect on the insulin stimulation of FAS promoter activity, wortmannin
and LY294002, which inhibit PI3-kinase, blocked insulin stimulation of
FAS promoter activity. Although the kinase dead p110 subunit of
PI3-kinase was ineffective, cotransfection of the expression vector for
the constitutively active p110 subunit resulted in elevated FAS
promoter activity in the absence of insulin and a loss of insulin
response of the FAS promoter. On the other hand, a dominant negative
p85 subunit of PI3-kinase inhibited FAS promoter activity and abolished
insulin stimulation of the FAS promoter. Moreover, cotransfection of
protein kinase B (PKB)/akt, a downstream kinase of the PI3-kinase,
stimulated FAS promoter activity in the absence of insulin to a level
comparable to the insulin-stimulated level. Acting in a
dominant-inhibitory fashion, kinase dead PKB/akt inhibited FAS
promoter activity in the presence and absence of insulin. These results
suggest that insulin regulation of FAS transcription is mediated by the
PI3-kinaase signaling pathway and that PKB/akt is a downstream
effector.
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Prospective |
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TOPABSTRACTINTRODUCTIONHormonal and nutritional...Insulin response sequence of...Signal transduction pathway for...ProspectiveREFERENCES |
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). C/EBP
isoforms and HNF-3 were shown to bind to this region and may be
involved in dominant repression by insulin of the cAMP and
glucocorticoid-stimulated PEPCK transcription (O’Brien et al. 1995
). PI3-kinase, but not Ras-MAP kinase or p70 S6
kinase, is required for PEPCK gene repression by insulin
(Sutherland et al. 1995
). Genetic analysis in
Caenorhabditis elegans has shown that a forkhead
transcription factor daf-16 is regulated by a pathway consisting of
insulin receptor–like daf-2 and PI3-kinase–like age-1 (Paradis and Ruvkin 1998
). Human orthologues of daf-16, AFX and FKHR-L1
can be phosphorylated in vitro by PKB to inhibit forkhead transcription
factor (Brunet et al. 1999
, Kops et al. 1999
). On the other hand, prolactin promoter activity increases
by insulin treatment in GH3 cells, and GABP, which belongs to the Ets
family of transcription factors, was shown to interact with its defined
insulin response element (Ouyang et al. 1996
). In
addition, other transcription factors, such as c-Fos and STAT3,
have been reported to undergo insulin-dependent phosphorylation.
This raises the possibility of their having a role in
insulin-regulated gene expression (Ceresa and Pessin 1996
, Thompson et al. 1994
). It is plausible
that distinct transcription factors bind to their cognate response
elements to repress or activate insulin-responsive genes.
Understanding common mechanisms governing induction of FAS and
mitochondrial GPAT genes by nutritional and hormonal stimuli will shed
light on the process of triacylglycerol synthesis, which contributes to
increased fat storage and obesity.
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FOOTNOTES |
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2 Supported by grants DK36264 and DK52806 from the National Institutes of Health to H.S.S.
4 Abbreviations used: CAT, chloramphenicol acetyltransferase; FAS, fatty acid synthase; GPAT, glycerol-3-phosphate acyltransferase; PEPCK, phosphoenolpyruvate carboxykinase; PI, phosphatidylinositol; PKB, protein kinase B; PUFA, polyunsaturated fatty acids; SREBP, sterol regulatory element binding protein; USF, upstream stimulatory factors.;5>
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