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Molecular and Cellular Biology, May 1999, p. 3760-3768, Vol. 19, No. 5
U465 INSERM,
Received 21 September 1998/Returned for modification 4 December
1998/Accepted 28 January 1999
The transcription of genes encoding proteins involved in the
hepatic synthesis of lipids from glucose is strongly stimulated by
carbohydrate feeding. It is now well established that in the liver,
glucose is the main activator of the expression of this group of genes,
with insulin having only a permissive role. While ADD1/SREBP-1 has been
implicated in lipogenic gene expression through temporal association
with food intake and ectopic gain-of-function experiments, no genetic
evidence for a requirement for this factor in glucose-mediated gene
expression has been established. We show here that the transcription of
ADD1/SREBP-1c in primary cultures of hepatocytes is controlled
positively by insulin and negatively by glucagon and cyclic AMP,
establishing a link between this transcription factor and carbohydrate
availability. Using adenovirus-mediated transfection of a powerful
dominant negative form of ADD1/SREBP-1c in rat hepatocytes, we
demonstrate that this factor is absolutely necessary for the
stimulation by glucose of L-pyruvate kinase, fatty acid
synthase, S14, and acetyl coenzyme A carboxylase gene expression. These
results demonstrate that ADD1/SREBP-1c plays a crucial role in
mediating the expression of lipogenic genes induced by glucose and insulin.
Feeding rodents with a
high-carbohydrate diet induces in liver and adipose tissue the
expression of a number of genes coding for proteins involved in energy
storage. In the liver, the presence of elevated concentrations of both
glucose and insulin is necessary to induce the expression of genes
involved in fatty acid synthesis from glucose, namely, the
L-pyruvate kinase (L-PK), fatty acid synthase (FAS),
acetyl coenzyme A (acetyl-CoA) carboxylase (ACC), and S14 genes
(10, 33). However, their roles are different. Glucose
stimulates the transcriptional activity of the promoter of these genes.
We have shown previously that glucose must be metabolized to have its
transcriptional effect and that glucose-6-phosphate is a candidate as
the signal metabolite (9, 23, 26). Insulin is not a direct
mediator of the transcriptional response but is permissive to glucose
action in hepatocytes through the induction of glucokinase gene
expression, allowing glucose phosphorylation (5, 26).
Glucose response elements (GlRE) have been identified in the L-PK and
S14 promoters. They consist of two copies of a motif related to the
consensus binding site 5'-CACGTG-3' (E box) separated by five
nucleotides (33). E boxes found in the L-PK and S14 GlRE bind to a transcription factor of the
basic-helix-loop-helix-leucine zipper (b-HLH-LZ) family. Among the
transcription factors belonging to this class of proteins, upstream
stimulatory factor/major late transcription factor (designated
USF) has been implicated as the mediator of glucose action. USF was
first found as a protein binding to the adenovirus (Ad) late promoter
and subsequently found to bind to many other gene promoters. The tissue
distribution of USF is ubiquitous and does not seem to be altered by
the nutritional or hormonal status. For the two genes considered (L-PK
and S14), binding of USF on the E box of the GlRE has been demonstrated in vitro, exclusive of other transcription factors (33). In hepatoma cells, overexpression of native USF proteins synthesized from
expression vectors can act as transactivators of the L-PK promoter via
the GlRE (20). However, a role for USF as the factor responsible for the glucose responsiveness of the L-PK and S14 genes is
disputed since both supportive and contradictory data have been
presented (15, 21). Moreover, to our knowledge, no link has
been established between glucose activation of gene expression and a
change in the transcriptional activity of USF. The reasons for these
conflicting results are not entirely clear but could indicate that a
factor other than USF is involved in the glucose responsiveness of
glycolytic and lipogenic genes.
We reasoned that this factor might be ADD1/SREBP-1c (adipocyte
determination and differentiation factor 1/sterol regulatory element
binding protein). ADD1/SREBP-1c belongs to a family of transcription
factors originally identified as involved in the regulation of genes by
the cellular availability in cholesterol (2). Three members
of the SREBP family have been described. SREBP-1a and SREBP-1c are
encoded by a single gene through the use of alternative transcription
start sites and differ in the first exon (31). In rat
adipocytes, SREBP-1c was independently described as a factor involved
in adipocyte determination and differentiation and called ADD1
(32). The third member of the family, SREBP-2, is derived
from a different gene (2).
SREBPs are bound in a precursor form to the endoplasmic reticulum and
nuclear membranes when the membrane concentration of cholesterol is
high. When the concentration of cholesterol decreases, the precursor
form is cleaved by a complex mechanism involving two proteolytic
cleavages and a protein sensor for the cholesterol concentration
(2). The mature form migrates inside the nucleus, where it
binds to the sterol response element (SRE), 5'-ATCACCCAC-3', on the promoters of genes involved in cholesterol uptake,
such as the low-density lipoprotein receptor gene, or in
cholesterol synthesis, such as the cytoplasmic
hydroxymethylglutaryl-CoA synthase or hydroxymethylglutaryl-CoA
reductase gene (34, 35). SREBPs are b-HLH-LZ
transcription factors, but in contrast to other members of the same
family, they are able to bind both to SRE and to E boxes due to the
presence of a tyrosine in place of an arginine in their basic domain
(18).
Various results suggest that ADD1/SREBP-1c, the most abundant form of
SREBPs in liver and adipose tissue, also controls the genes involved in
fatty acid synthesis. Overexpression of this factor in adipocyte cell
lines stimulates the expression of FAS (16, 17). Similarly,
its forced expression in transgenic mice led to a dramatically
increased expression of hepatic FAS and ACC and to liver steatosis,
whereas mRNAs for genes involved in cholesterol synthesis were barely
affected (29) and precluded the usual decrease in the mRNAs
of lipogenic enzymes observed during starvation (13).
Finally, it was recently reported that the expression of ADD1/SREBP-1c
itself is controlled positively by insulin in adipose tissue
(16) and by the nutritional status in mouse liver (high
expression and presence of the mature form of ADD1/SREBP-1c in the
nucleus in refed compared to starved animals) (13), thus
establishing a link between this transcription factor and the dietary
carbohydrate status.
The aims of this study were thus (i) to identify in primary cultures of
hepatocytes the factors which regulate the expression of ADD1/SREBP-1c
and (ii) to test the hypothesis that ADD1/SREBP-1c is involved in the
regulation of glucose-induced genes of the glycolytic/lipogenic
pathway. For this purpose, an Ad vector was used, allowing us to
express a dominant negative form of ADD1/SREBP-1c in cultured
hepatocytes and subsequently monitor the endogenous expression of
glucose-induced genes. We show that insulin and glucagon are,
respectively, positive and negative transcriptional regulators of
ADD1/SREBP-1c expression and that this transcription factor is indeed
necessary for the glucose-induced expression of the FAS, S14, ACC, and
L-PK genes.
Animals.
Animal studies were conducted according to French
guidelines for the care and use of experimental animals. Female Wistar
rats (200 to 300 g [body weight]) from Iffa-Credo, L'Arbresle,
France, were used for isolation of hepatocytes. They were housed in
plastic cages at a constant temperature (22°C) with light from 0700 to 1900 h for at least 1 week before the experiments.
Preparation of recombinant Ad.
The dominant negative form of
ADD1 (ADD1-DN) (18) was subcloned into the
EcoRI-linearized pDK6 shuttle vector (7) under the control of the cytomegalovirus immediate-early promoter. Plasmid pDK6 ADD1-DN was cotransfected in 293 cells together with the ClaI-cut DNA of the E1a Hepatocyte isolation, culture, and treatment with recombinant
Ad.
Hepatocytes were isolated from fed rats by the collagenase
method (1). Cell viability was assessed by the trypan blue
exclusion test and was always higher than 85%. Hepatocytes were seeded
at a density of 8 × 106 cells/dish in 100-mm-diameter
petri dishes in medium 199 (M199) with Earle's salts (Gibco/BRL,
Paisley, United Kingdom) supplemented with penicillin (100 U/ml),
streptomycin (100 µg/ml), 0.1% (wt/vol) bovine serum albumin, 2%
(vol/vol) Ultroser G (Gibco/BRL), 100 nM dexamethasone (Sigma, St.
Louis, Mo.), 1 nM insulin (Actrapid; Novo Nordisk, Copenhagen,
Denmark), and 100 nM triiodothyronine (T3; Sigma). After
cell attachment (4 h), the medium was replaced by a medium similar to
the plating medium but free of Ultroser G and albumin and the cells
were cultured in various conditions as described in the figure legends.
In the experiments in which gene expression was induced by a high
glucose concentration, hepatocytes were first cultured for 16 h in
the presence of 100 nM dexamethasone, 100 nM insulin, and 100 nM
T3 and a nonstimulatory glucose concentration (5 mM) in
order to induce the expression of glucokinase. Then a high (25 mM)
glucose concentration was used.
Staining techniques.
To detect the presence of lipid
droplets, hepatocytes were fixed at the end of the culture period by
10% formaldehyde in phosphate-buffered saline and stained with oil red
O as described elsewhere (11). To assess the efficiency of
gene transfer when the Ad vector was used, hepatocytes were cultured
for 48 h after a 2-h treatment with Ad Glucose-6-phosphate assay.
The intracellular concentration
of glucose-6-phosphate in cultured hepatocytes was measured by
previously described spectrophotometric assay (23). Results
are expressed as means ± standard errors of the means for two
different cultures, each set up in triplicate.
Isolation of total RNA and Northern blot hybridization.
Total cellular RNAs were extracted from cultured hepatocytes by using
guanidine thiocyanate (3) and prepared for Northern blot
hybridization as previously described (4). Labeling of each
DNA probe with [ Nuclear run-on transcription assay.
Nucleus isolation and
nuclear run-on transcription experiments were performed as described by
Dugail et al. (6).
Gel mobility shift assay.
The full-length cDNA encoding the
43-kDa human USF (12) was a kind gift from P. Pognonec
(Nice, France). USF cDNA subcloned into pBluescript KS+ and
ADD1-403 (18) and ADD1-403-DN cloned into pSVSport1 were translated by using the TNT SP6 (ADD1) or T7 (USF) coupled reticulocyte lysate system (Promega). The DNA probe used was double-stranded oligonucleotides derived from the wild-type sequence found between The cDNA probe used recognizes both the SREBP-1c and SREBP-1a
isoforms. In rodent liver, the expression of ADD1/SREBP-1c predominates over that of SREBP-1a by a 9:1 ratio (31), and SREBP-1a mRNA abundance is usually quantified by RNase protection. Moreover the
expression of SREBP-1a is not affected by a fasting-refeeding experiment (13). We have thus considered that the signal
obtained in Northern blots was representative of ADD1/SREBP-1c expression.
In rats, as previously described for mice (13), a 24-hour
starvation period induces a nearly total disappearance of ADD1/SREBP-1c mRNA whereas refeeding with a high-carbohydrate diet induces its strong
appearance (results not shown). To identify the factors (hormones and
substrates) which control ADD1/SREBP-1c gene expression, we conducted a
series of experiments with primary cultures of rat hepatocytes. Since
in vivo a high-carbohydrate diet induces ADD1/SREBP-1c gene expression,
obvious candidates were insulin, a hormone involved in metabolic
adaptations in the fed state, and glucose itself. Hepatocytes cultured
for 16 h in the absence of insulin did not express ADD1/SREBP-1c
mRNA. Addition of insulin led in 6 h to a clear-cut increase in
its expression, with a nearly maximal effect for an insulin
concentration of 1 nM (Fig. 1A). This
finding strongly suggests that insulin acts through its own receptor to
stimulate SREBP-1c gene expression. A time course performed at the
highest dose of insulin indicated that between 2 and 4 h after
insulin addition, SREBP-1c gene expression was increased (Fig. 1B). To
test a potential effect of glucose, hepatocytes were cultured for
16 h in the absence or presence of insulin and in the presence of
a basal glucose concentration (5 mM). Switching the medium glucose
concentration from a basal (5 mM) to a high (25 mM) level did not
increase in 6 h SREBP-1c expression in the absence or in the
presence of insulin (Fig. 1C), whereas a high glucose concentration had
the usual stimulating effect on FAS gene expression in the presence of
insulin. Thus, insulin but not glucose is likely responsible for the
stimulating effect of a high-carbohydrate diet observed in vivo on
ADD1/SREBP-1c expression.
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
ADD1/SREBP-1c Is Required in the Activation of
Hepatic Lipogenic Gene Expression by Glucose
ABSTRACT
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
INTRODUCTION
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
MATERIALS AND METHODS
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
Ad vector, Ad gal-nls
(25). Recombinant Ad ADD1-DN plaques were detected by PCR
amplification of viral DNA using ADD1 primers, and one clone was
further amplified in 293 cells. The Ad vector Ad null, for which the
expression cassette contains the major late promoter with no exogenous
gene, was used as a control (19). Ad 
-gal, which contains
the Escherichia coli lacZ gene coding for -galactosidase,
driven by the Rous sarcoma virus promoter (19) was also used
to determine the efficiency of Ad-mediated gene transfer in cultured
hepatocytes. The Ad vectors were propagated in 293 cells, purified by
cesium chloride density centrifugation, and stored as previously
described (19).
-gal, and Ad ADD1-DN ranging
from 0.3 to 30 PFU/cell. The medium was then replaced by fresh medium
containing hormones and either 5 or 25 mM glucose.
-gal (30 PFU/cell). At
the end of the culture, expression of the -galactosidase gene was
demonstrated by incubating fixed hepatocytes at 37°C for 30 min in a
chromogenic solution containing 35 mM
K3Fe(CN)6-K4Fe(CN)6, 2 mM MgCl2, and 1 mg of
5-bromo-4-chloro-2-indolyl--D-galactopyranoside per ml.
The efficiency of gene transfer was determined by counting clear and
blue cells.
-32P]dCTP was performed by random
priming (Rediprime labeling kit; Amersham, Little Chalfont, United
Kingdom). Autoradiograms of Northern blots were scanned and quantified
with an image processor program. FAS and
glyceraldehyde-3-phosphate dehydrogenase (GAPDH) cDNAs were as
previously described (4, 6). Albumin and S14 cDNAs were kind
gifts from J. L. Danan (Meudon, France) and R. Plannels
(Marseille, France), respectively. ADD1/SREBP-1c cDNA is as previously
described (16). Rat angiotensinogen (AGE) cDNA was purchased
from the American Type Culture Collection (Rockville, Md.). cDNA probes
for rat ACC, L-PK, and apolipoprotein AI (ApoAI) were prepared by
reverse transcriptase-mediated PCR from rat liver total RNA. The PCR
primers used were as follows: for ACC, upper primer
5'-TGAAGGCTGTGGTGATGGAT-3' and lower primer
5'-CCGTAGTGGTTGAGGTTGGA-3'; for ApoAI, upper primer
5'-CCGGAATTCATGAAAGCTGCAGTGTTGGCTGTG-3' and lower primer
5'-GCTCTAGACTCTAGGTTGCCCAGAACTCCTGAGT-3'; for L-PK, upper
primer 5'-ATGGAAGGGCCAGCGGGATACCTTCGA-3' and lower primer
5'-GGATACGCTCAGCACCCGCATGATGTT-3'.
95
and 53 relative to the transcription start site in the FAS promoter
sequence
5'-GCCTGGGCGGCGCAGCCAAGCTGTCAGCCCATGTGGCGTGGC-3', containing an E-box-like sequence (underlined). Only the upper strand is shown. Oligonucleotides were end labeled by using
[
-32P]ATP and T4 polynucleotide kinase and gel
purified. For binding assays, reactions were performed for 30 min at
37°C in a 20-µl volume containing 20 mM Tris HCl (pH 7.5), 5%
glycerol, 0.02% Nonidet P-40, 100 mM NaCl, 1 mM dithiothreitol, 5 mM
MgCl2, 1 µg of poly(dI/dC), and 50 to 100 fmol (typically
30,000 cpm) of 32P-labeled probe. Similar amounts of
ADD1-403 and USF proteins (estimated by [35S]methionine
incorporation performed in separate reactions) and increasing amounts
of ADD1-DN (1 to 6 µl of reticulocyte lysate) were added to the
binding reaction.
RESULTS
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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FIG. 1.
Effects of insulin and glucose on ADD1/SREBP-1c gene
expression in cultured hepatocytes. (A) Hepatocytes were cultured for
16 h in the presence of 5 mM glucose and then incubated for 6 h with or without insulin at a concentration of 1 to 100 nM in the
presence of 5 mM glucose. A representative Northern blot as well as the
quantification of blots obtained in three independent experiments is
shown. (B) Hepatocytes were cultured for 16 h in the presence of 5 mM glucose and then incubated with 100 nM insulin for 1 to 6 h.
(C) Hepatocytes were cultured for 16 h in the presence of 5 mM
glucose and then incubated for 6 h with 5 or 25 mM glucose in the
absence or presence of 100 nM insulin. Total RNAs were extracted and
analyzed for the concentration of ADD1/SREBP-1c, FAS, and albumin
mRNAs. The Northern blots are representative of three culture
experiments. Statistical significance was analyzed by Student's
t test for unpaired data. When quantified, the
concentrations of ADD1/SREBP-1c mRNA are expressed as a ratio to the
corresponding albumin signal. ** and ***, difference
statistically significant for P < 0.01 and
P < 0.001, respectively.
Glucagon inhibits the insulin effect on many hepatic processes, including expression of specific genes through the generation of cyclic AMP (cAMP) and the activation of protein kinase A. For instance, expression of the phosphoenolpyruvate carboxykinase (PEPCK) gene is inhibited by insulin and activated by glucagon (27). We therefore tested the effect of glucagon on insulin-induced ADD1/SREBP-1c expression. Hepatocytes were cultured for 16 h in the presence of 5 mM glucose and 100 nM insulin and then treated for a further 24 h in the absence or presence of 1 µM glucagon. As shown in Fig. 2A, ADD1/SREBP-1c expression is dramatically decreased by glucagon, whereas expression of the PEPCK gene, taken as a positive control, is strongly induced. The same effect is observed with dibutyryl-cAMP (Fig. 2B): in 6 h, 5 µM dibutyryl-cAMP is sufficient to profoundly inhibit ADD1/SREBP-1c gene expression and to markedly stimulate PEPCK gene expression. These results show that glucagon, through the production of cAMP, inhibits the insulin effect on ADD1/SREBP-1c expression. Run-on experiments were then performed with nuclei isolated from hepatocytes cultured for 1 h in the presence of insulin or glucagon (after previous insulin induction). The PEPCK gene was taken as a control. As shown previously, insulin decreases and glucagon increases the PEPCK gene transcription rate (Fig. 3) (27). On the same nuclei, insulin increases (Fig. 3A) and glucagon decreases (Fig. 3B) the ADD1/SREBP-1c transcription rate. This finding demonstrates that the hormonal effects described above involve a transcriptional mechanism, although we cannot exclude the possibility that the ADD1/SREBP-1c mRNA half-life is also affected by the hormones. To assess whether the effects of insulin and dibutyryl-cAMP on ADD1/SREBP-1c gene expression were dependent on ongoing protein synthesis, experiments were performed in the presence of cycloheximide. As shown in Fig. 4, inhibition of protein synthesis precluded the respective activatory and inhibitory effects of insulin and glucagon on ADD1/SREBP-1c gene expression, whereas the basal expression of albumin was not affected. This result suggests that ongoing protein synthesis is necessary for the hormone actions.
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Changes in the insulin/glucagon ratio are thus powerful regulators of ADD1/SREBP-1c expression and hence of genes which depend on the presence of ADD1/SREBP-1c for transcriptional activation. However, it is also clear from previous results and those of the present experiment (Fig. 1C) that the presence of insulin and thus the expression of ADD1/SREBP-1c are not sufficient by themselves to induce the expression of lipogenic genes such as the FAS gene in hepatocytes.
To test the hypothesis that the mature form of ADD1/SREBP-1c is involved in the glucose activation of glycolytic and lipogenic genes, we used a strategy involving the expression in cultured hepatocytes of a dominant negative form of ADD1/SREBP-1c. The dominant negative form of ADD1/SREBP-1c consists of the amino-terminal fragment of ADD1/SREBP-1c (ADD1-403), for which the wild type has a maximal transcriptional activity, but containing an alanine mutation at amino acid 320 (17). This mutation abolishes the binding of ADD1-403 to both SRE and E boxes but still allows dimerization, leading to a decreased availability of endogenous ADD1/SREBP-1c. The efficiency of this dominant negative form to counteract the transcriptional activity of ADD1/SREBP-1c has previously been established in transient transfections in cell lines (17).
Since ADD1/SREBP-1c, like USF, is a b-HLH-LZ protein, it was important to demonstrate first that ADD1-DN was not able to dimerize with USF, thus impeding USF binding on an E box. Figure 5 shows results of a gel shift experiment using an oligonucleotide probe containing the E-box sequence of the proximal promoter of the FAS gene. Both ADD1/SREBP-1c and USF are able to bind to this oligonucleotide, as shown by the retarded complex observed in both cases compared to the nonprogrammed reticulocyte lysate. Increasing amounts of ADD1-DN in the presence of ADD1/SREBP-1c are able to decrease the retarded complex as previously demonstrated (18), whereas no effect was observed in the presence of USF. This shows that ADD1-DN does not interfere with USF binding.
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ADD1-DN was incorporated into an Ad vector in order to transduce
primary cultures of hepatocytes. In preliminary experiments, in which
the same Ad containing a -galactosidase gene rather than ADD1-DN was
used, more than 90% of the hepatocytes expressed -galactosidase at
an infection titer of 30 PFU/cell (results not shown).
As shown in Fig. 6A, transduction of cultured hepatocytes with increasing titers of Ad led to a proportional expression of ADD1-DN. Expression of the endogenous wild-type ADD1/SREBP-1c was slightly decreased in the presence of the highest viral titer. Transduction of hepatocytes with an Ad which does not contain the ADD1-DN gene had no effect by itself (Fig. 6A). It must be pointed out that it is not possible to show in gel shift experiments that the binding of ADD1/SREBP-1c to its site is decreased when nuclear extracts from the infected cells are used, since the abundance of ADD1/SREBP-1 is too low to be detected.
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We then used the Ad-mediated ADD1-DN expression to test in cultured hepatocytes the specific involvement of the ADD1/SREBP-1c transcription factor in the control by glucose of glycolytic and lipogenic gene expression.
As shown in Fig. 6B, switching the medium glucose concentration from a
basal (5 mM) to a high (25 mM) concentration induces in 24 h the
expression of FAS, ACC, S14, and L-PK genes as previously described,
whereas it has no effect on control genes such as the AGE, GAPDH,
ApoAI, or -actin gene. Expression of the dominant negative form of
ADD1/SREBP-1c in a dose-dependent fashion prevents in a proportional
manner the effect of glucose on FAS, ACC, S14, and L-PK gene expression
but has no effect on control genes (Fig. 6B). Transduction of
hepatocytes with an Ad which does not contain the ADD1-DN gene has no
effect (Fig. 6B).
Since the effect of glucose on gene expression is dependent on its phosphorylation by glucokinase, we also checked that the expression of ADD1-DN was not affecting this step. Switching the glucose medium from 5 to 25 mM induced after 2 h an increase in glucose-6-phosphate concentration from 0.39 ± 0.01 to 1.89 ± 0.01 nmol/106 hepatocytes in control hepatocytes. In hepatocytes transduced previously with ADD1-DN and cultured for 24 h in the presence of 5 mM glucose, a switch for 2 h to 25 mM glucose led to a similar increase in glucose-6-phosphate concentration: 2.34 ± 0.16 nmol/106 hepatocytes (difference not significant).
To confirm that ADD1/SREBP-1c is involved in the glucose-mediated activation of gene expression and does not impair a general transcription mechanism, we took advantage of the fact that S14 gene expression can be induced independently by glucose and by T3, the two effects being additive (22). In hepatocytes cultured in a low-glucose (5 mM) medium and in the absence of T3, S14 gene expression was barely detectable (Fig. 7). Addition of T3 led to a clear-cut induction of S14 gene expression. Interestingly, this effect of T3 was not affected by the expression of ADD1-DN (Fig. 7) at a dose which totally prevented the glucose effect (Fig. 6B).
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Finally, we investigated whether the inhibition of ADD1/SREBP-1c had functional effects in terms of lipid synthesis in hepatocytes. Culture for 48 h in the presence of 5 mM glucose does not lead to lipid accumulation in hepatocytes (Fig. 8). In contrast, in the presence of 25 mM glucose, red-colored lipid droplets are clearly visible in hepatocytes. Transduction of hepatocytes with an Ad which does not contain the ADD1-DN gene has no effect on lipid accumulation in the presence of 25 mM glucose whereas lipid accumulation is prevented by the expression of ADD1-DN. This finding demonstrates that the absence of a functional ADD1/SREBP-1c totally precludes lipid synthesis even in the presence of a high glucose concentration.
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DISCUSSION |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Adaptation of energy metabolism to the nutritional environment is essential for survival. The liver has a central role in these metabolic adaptations: it is the main organ which produces glucose when this substrate is not provided by the diet, and in a period of glucose availability, it will synthesize glycogen or lipids, the latter being ultimately stored as triglycerides in adipose tissue. Regulation of liver metabolism by a high-carbohydrate diet involves both posttranslational and transcriptional mechanisms. Genes coding for proteins involved in the synthesis of fatty acids from glucose such as L-PK, FAS, ACC, and S14 are among those which are particularly responsive in the liver to feeding large amounts of carbohydrates. Insulin has long been considered the major regulator of their expression. More recently, a specific transcriptional role for glucose has been recognized, with insulin having only a permissive role. However, nuclear factors allowing establishment of a link between glucose and the transcription processes were largely unknown (10, 33).
ADD1/SREBP-1c has been recently proposed as a factor essential to the expression of lipogenic enzymes; among the various isoforms of SREBPs, ADD1/SREBP-1c is expressed primarily in the liver and adipose tissue of rodents fed a normal chow diet (31), whereas the expression of SREBP-2, which controls the expression of genes involved in cholesterol synthesis (14), is increased mainly in conditions of strong cellular cholesterol depletion (28) and SREBP-1a is expressed primarily in cell lines (31). In the liver, the expression of ADD1/SREBP-1c and the expression of lipogenic enzymes in starve/refeed cycles follow the same pattern. The forced expression of the mature form of ADD1/SREBP-1c in both an adipocyte cell line and livers of transgenic mice stimulates the transcriptional activation of genes involved in lipid synthesis (16, 17, 29). However, loss-of-function experiments using knockouts of the SREBP-1 gene in mice were less informative: most mice died, and the expression of lipogenic enzymes in the survivors was normal or only slightly decreased (30).
We have now analyzed the role of ADD1/SREBP-1c, taking advantage of a very effective dominant negative form which could be expressed in primary cultured hepatocytes by using an Ad vector, thus allowing us to study endogenous rather than transfected promoter activity. We demonstrate that ADD1/SREBP-1c is essential for the induction by glucose of genes of fatty acid metabolism and that in its absence, lipid synthesis in the liver is dramatically blunted. This result establishes for the first time a link between a transcription factor and the well-known glucose effect on lipogenic enzyme gene expression. Insulin has a permissive role in the system by stimulating the transcription of ADD1/SREBP-1c in the liver. During carbohydrate feeding, this effect would be favored by the decreased glucagon concentration since the transcription of ADD1/SREBP-1c is down-regulated by this hormone. This hormonal regulation explains why ADD1/SREBP-1c expression is low in the livers of starved rodents but greatly increased after a carbohydrate refeeding (13).
The presence of insulin is not sufficient to induce the expression of these genes, which raises an intriguing question: what is the specific role of glucose in ADD1/SREBP-1c activation? As for other members of the SREBP family, ADD1/SREBP-1c is synthesized as a precursor form bound in the membranes of endoplasmic reticulum and nuclear membranes. The precursor forms of SREBP-2 and SREBP-1a are then cleaved by specific proteases in case of cholesterol cellular depletion, and the mature form is translocated into the nucleus (2). As noted previously, ADD1/SREBP-1c cleavage may be regulated by different signals linked to the nutritional environment (13, 16). The finding that refeeding starved animals with a carbohydrate-rich diet induces a large increase in the amount of mature ADD1/SREBP-1c in the liver nuclei (13) suggests that glucose can activate the proteolytic cleavage of SREBP-1c and increase its nuclear availability. Alternatively, ADD1/SREBP-1c might be constitutively cleaved or cleaved in the presence of insulin and transferred into the nucleus, but its full transcriptional activity would require a further activation linked in an unknown way to glucose metabolism. Along this line, we have recently suggested that the activation of glycolytic and lipogenic gene expression by glucose requires a dephosphorylation process (8).
The next question which arises is the identity of the DNA response
element by which ADD1/SREBP-1c could control the expression of these
genes. Since one of their common features is a responsiveness to
glucose, one obvious possibility is the involvement of the GlRE itself.
For the two genes in which it has been clearly identified, L-PK and
S14, the GlRE consists of two motifs related to E boxes (33). ADD1/SREBP-1c is indeed able to bind to E boxes
(18). Furthermore, in NIH 3T3 cells, cotransfection of an
ADD1/SREBP-1c expression vector stimulated transcription of a
chloramphenicol acetyltransferase reporter gene linked to four copies
of the S14 GlRE (18). Although it has never been
demonstrated that the L-PK gene promoter is transactivated by SREBP,
its GlRE is very similar to that described for the S14 gene, and we
have verified in gel retardation experiments that an oligonucleotide
corresponding to this GlRE is able to bind the purified active form of
ADD1/SREBP-1c (results not shown). For the FAS gene, a GlRE has not yet
been identified. However, in its proximal promoter an insulin response element involving an E box at 64 to 59 has been identified in adipocyte cell lines (24). Since these cells were cultured
in the presence of glucose, it cannot be ruled out that the insulin effect on the FAS gene promoter is in fact secondary to a stimulation of glucose metabolism as described for adipose tissue (9). ADD1/SREBP-1c was identified as the factor involved in insulin responsiveness through its binding to this E box (16),
emphasizing its potential role in the control of FAS expression by
nutritional conditions.
Although ADD1/SREBP-1c and SREBP-2 can bind to both SRE and the E box, ADD1/SREBP-1c would control the expression of genes involved in lipid synthesis through the presence of an E box whereas SREBP-2 controls the genes involved in cholesterol metabolism through the presence of an SRE. The reasons for this difference remain to be elucidated.
In conclusion, we propose the following scheme to explain the large increase in the expression of glycolytic and lipogenic gene expression in the liver after carbohydrate feeding. The high concentrations of insulin and glucose in the portal vein cooperate in a subtle interplay. Insulin stimulates the transcription of two factors, glucokinase and ADD1/SREBP-1c, necessary for the effect of glucose on gene expression. Glucokinase in the presence of a high glucose concentration then allows the generation of a signal metabolite for which the ultimate target would be the activation of ADD1/SREBP-1c, either through increased proteolytic cleavage or through activation of the mature form.
Finally, we point out that the use of Ad-mediated expression of the dominant negative form of ADD1/SREBP-1c in primary cultures of hepatocytes is a valuable tool for identifying other genes which might be regulated by this transcription factor and/or by glucose.
| |
ACKNOWLEDGMENTS |
|---|
We thank Jack Gauldie (McMaster University) for the generous gift
of PDK6 and Marc Eloit (URA INRA, ENVA, Maisons-Alfort, France) for Ad
gal-nls.
Marc Foretz is a recipient of a doctoral fellowship from the Ministère de l'Enseignement Supérieur et de la Recherche. Pascal Ferré is financed by the Centre National de la Recherche Scientifique. This work was supported in part by the grant 97/3011 from the EEC Fair program, by the Institut Necker, and by the Association Francaise des Myopathies.
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FOOTNOTES |
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* Corresponding author. Mailing address: U465 INSERM, Institut Biomédical des Cordeliers, 15 rue de l'école de Médecine, 75270 Paris Cedex 06, France. Phone: 33 1 42 34 69 22. Fax: 33 1 40 51 85 86. E-mail: pferre{at}planete.net.
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REFERENCES |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Molecular and Cellular Biology, May 1999, p. 3760-3768, Vol. 19, No. 5
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Nadeau, K. J., Leitner, J. W., Gurerich, I., Draznin, B.
(2004). Insulin Regulation of Sterol Regulatory Element-binding Protein-1 Expression in L-6 Muscle Cells and 3T3 L1 Adipocytes. J. Biol. Chem.
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Kim, S.-Y., Kim, H.-i., Kim, T.-H., Im, S.-S., Park, S.-K., Lee, I.-K., Kim, K.-S., Ahn, Y.-H.
(2004). SREBP-1c Mediates the Insulin-dependent Hepatic Glucokinase Expression. J. Biol. Chem.
279: 30823-30829
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Nagata, R., Nishio, Y., Sekine, O., Nagai, Y., Maeno, Y., Ugi, S., Maegawa, H., Kashiwagi, A.
(2004). Single Nucleotide Polymorphism (-468 Gly to Ala) at the Promoter Region of Sterol Regulatory Element-binding Protein-1c Associates with Genetic Defect of Fructose-induced Hepatic Lipogenesis. J. Biol. Chem.
279: 29031-29042
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Commerford, S. R., Peng, L., Dube, J. J., O'Doherty, R. M.
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287: R218-R227
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Seo, J. B., Moon, H. M., Noh, M. J., Lee, Y. S., Jeong, H. W., Yoo, E. J., Kim, W. S., Park, J., Youn, B.-S., Kim, J. W., Park, S. D., Kim, J. B.
(2004). Adipocyte Determination- and Differentiation-dependent Factor 1/Sterol Regulatory Element-binding Protein 1c Regulates Mouse Adiponectin Expression. J. Biol. Chem.
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Dentin, R., Pegorier, J.-P., Benhamed, F., Foufelle, F., Ferre, P., Fauveau, V., Magnuson, M. A., Girard, J., Postic, C.
(2004). Hepatic Glucokinase Is Required for the Synergistic Action of ChREBP and SREBP-1c on Glycolytic and Lipogenic Gene Expression. J. Biol. Chem.
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Collier, J. J., Scott, D. K.
(2004). Sweet Changes: Glucose Homeostasis Can Be Altered by Manipulating Genes Controlling Hepatic Glucose Metabolism. Mol. Endocrinol.
18: 1051-1063
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Wang, Y., Jones Voy, B., Urs, S., Kim, S., Soltani-Bejnood, M., Quigley, N., Heo, Y.-R., Standridge, M., Andersen, B., Dhar, M., Joshi, R., Wortman, P., Taylor, J. W., Chun, J., Leuze, M., Claycombe, K., Saxton, A. M., Moustaid-Moussa, N.
(2004). The Human Fatty Acid Synthase Gene and De Novo Lipogenesis Are Coordinately Regulated in Human Adipose Tissue. J. Nutr.
134: 1032-1038
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Seo, J. B., Moon, H. M., Kim, W. S., Lee, Y. S., Jeong, H. W., Yoo, E. J., Ham, J., Kang, H., Park, M.-G., Steffensen, K. R., Stulnig, T. M., Gustafsson, J.-A., Park, S. D., Kim, J. B.
(2004). Activated Liver X Receptors Stimulate Adipocyte Differentiation through Induction of Peroxisome Proliferator-Activated Receptor {gamma} Expression. Mol. Cell. Biol.
24: 3430-3444
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Stoeckman, A. K., Ma, L., Towle, H. C.
(2004). Mlx Is the Functional Heteromeric Partner of the Carbohydrate Response Element-binding Protein in Glucose Regulation of Lipogenic Enzyme Genes. J. Biol. Chem.
279: 15662-15669
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Hummasti, S., Laffitte, B. A., Watson, M. A., Galardi, C., Chao, L. C., Ramamurthy, L., Moore, J. T., Tontonoz, P.
(2004). Liver X receptors are regulators of adipocyte gene expression but not differentiation: identification of apoD as a direct target. J. Lipid Res.
45: 616-625
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Duran-Sandoval, D., Mautino, G., Martin, G., Percevault, F., Barbier, O., Fruchart, J.-C., Kuipers, F., Staels, B.
(2004). Glucose Regulates the Expression of the Farnesoid X Receptor in Liver. Diabetes
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Rishi, V., Gal, J., Krylov, D., Fridriksson, J., Boysen, M. S., Mandrup, S., Vinson, C.
(2004). SREBP-1 Dimerization Specificity Maps to Both the Helix-Loop-Helix and Leucine Zipper Domains: USE OF A DOMINANT NEGATIVE. J. Biol. Chem.
279: 11863-11874
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Matsuzaka, T., Shimano, H., Yahagi, N., Amemiya-Kudo, M., Okazaki, H., Tamura, Y., Iizuka, Y., Ohashi, K., Tomita, S., Sekiya, M., Hasty, A., Nakagawa, Y., Sone, H., Toyoshima, H., Ishibashi, S., Osuga, J.-i., Yamada, N.
(2004). Insulin-Independent Induction of Sterol Regulatory Element-Binding Protein-1c Expression in the Livers of Streptozotocin-Treated Mice. Diabetes
53: 560-569
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Ascencio, C., Torres, N., Isoard-Acosta, F., Gomez-Perez, F. J., Hernandez-Pando, R., Tovar, A. R.
(2004). Soy Protein Affects Serum Insulin and Hepatic SREBP-1 mRNA and Reduces Fatty Liver in Rats. J. Nutr.
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Demozay, D., Rocchi, S., Mas, J.-C., Grillo, S., Pirola, L., Chavey, C., Van Obberghen, E.
(2004). Fatty Aldehyde Dehydrogenase: POTENTIAL ROLE IN OXIDATIVE STRESS PROTECTION AND REGULATION OF ITS GENE EXPRESSION BY INSULIN. J. Biol. Chem.
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Wu, C., Okar, D. A., Stoeckman, A. K., Peng, L.-J., Herrera, A. H., Herrera, J. E., Towle, H. C., Lange, A. J.
(2004). A Potential Role for Fructose-2,6-Bisphosphate in the Stimulation of Hepatic Glucokinase Gene Expression. Endocrinology
145: 650-658
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Roth, U., Curth, K., Unterman, T. G., Kietzmann, T.
(2004). The Transcription Factors HIF-1 and HNF-4 and the Coactivator p300 Are Involved in Insulin-regulated Glucokinase Gene Expression via the Phosphatidylinositol 3-Kinase/Protein Kinase B Pathway. J. Biol. Chem.
279: 2623-2631
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Ono, H., Shimano, H., Katagiri, H., Yahagi, N., Sakoda, H., Onishi, Y., Anai, M., Ogihara, T., Fujishiro, M., Viana, A. Y.I., Fukushima, Y., Abe, M., Shojima, N., Kikuchi, M., Yamada, N., Oka, Y., Asano, T.
(2003). Hepatic Akt Activation Induces Marked Hypoglycemia, Hepatomegaly, and Hypertriglyceridemia With Sterol Regulatory Element Binding Protein Involvement. Diabetes
52: 2905-2913
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Berti, J. A., Casquero, A. C., Patricio, P. R., Bighetti, E. J. B., Carneiro, E. M., Boschero, A. C., Oliveira, H. C. F.
(2003). Cholesteryl ester transfer protein expression is down-regulated in hyperinsulinemic transgenic mice. J. Lipid Res.
44: 1870-1876
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Borradaile, N. M., de Dreu, L. E., Huff, M. W.
(2003). Inhibition of Net HepG2 Cell Apolipoprotein B Secretion by the Citrus Flavonoid Naringenin Involves Activation of Phosphatidylinositol 3-Kinase, Independent of Insulin Receptor Substrate-1 Phosphorylation. Diabetes
52: 2554-2561
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Olsson, B., Bohlooly-Y, M., Brusehed, O., Isaksson, O. G. P., Ahren, B., Olofsson, S.-O., Oscarsson, J., Tornell, J.
(2003). Bovine growth hormone-transgenic mice have major alterations in hepatic expression of metabolic genes. Am. J. Physiol. Endocrinol. Metab.
285: E504-E511
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Latasa, M.-J., Griffin, M. J., Moon, Y. S., Kang, C., Sul, H. S.
(2003). Occupancy and Function of the -150 Sterol Regulatory Element and -65 E-Box in Nutritional Regulation of the Fatty Acid Synthase Gene in Living Animals. Mol. Cell. Biol.
23: 5896-5907
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Yamada, K., Kawata, H., Shou, Z., Mizutani, T., Noguchi, T., Miyamoto, K.
(2003). Insulin Induces the Expression of the SHARP-2/Stra13/DEC1 Gene via a Phosphoinositide 3-Kinase Pathway. J. Biol. Chem.
278: 30719-30724
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Seo, J. B., Noh, M. J., Yoo, E. J., Park, S. Y., Park, J., Lee, I. K., Park, S. D., Kim, J. B.
(2003). Functional Characterization of the Human Resistin Promoter with Adipocyte Determination- and Differentiation-Dependent Factor 1/Sterol Regulatory Element Binding Protein 1c and CCAAT Enhancer Binding Protein-{alpha}. Mol. Endocrinol.
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Oh, S.-Y., Park, S.-K., Kim, J.-W., Ahn, Y.-H., Park, S.-W., Kim, K.-S.
(2003). Acetyl-CoA Carboxylase {beta} Gene Is Regulated by Sterol Regulatory Element-binding Protein-1 in Liver. J. Biol. Chem.
278: 28410-28417
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Diraison, F., Yankah, V., Letexier, D., Dusserre, E., Jones, P., Beylot, M.
(2003). Differences in the regulation of adipose tissue and liver lipogenesis by carbohydrates in humans. J. Lipid Res.
44: 846-853
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Mur, C., Arribas, M., Benito, M., Valverde, A. M.
(2003). Essential Role of Insulin-Like Growth Factor I Receptor in Insulin-Induced Fetal Brown Adipocyte Differentiation. Endocrinology
144: 581-593
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Zhang, Y., Yin, L., Hillgartner, F. B.
(2003). SREBP-1 integrates the actions of thyroid hormone, insulin, cAMP, and medium-chain fatty acids on ACC{alpha} transcription in hepatocytes. J. Lipid Res.
44: 356-368
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Thomas, J., Bramlett, K. S., Montrose, C., Foxworthy, P., Eacho, P. I., McCann, D., Cao, G., Kiefer, A., McCowan, J., Yu, K.-l., Grese, T., Chin, W. W., Burris, T. P., Michael, L. F.
(2003). A Chemical Switch Regulates Fibrate Specificity for Peroxisome Proliferator-activated Receptor alpha (PPARalpha ) Versus Liver X Receptor. J. Biol. Chem.
278: 2403-2410
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Schuit, F., Flamez, D., De Vos, A., Pipeleers, D.
(2002). Glucose-Regulated Gene Expression Maintaining the Glucose-Responsive State of {beta}-Cells. Diabetes
51: S326-332
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Eto, K., Yamashita, T., Matsui, J., Terauchi, Y., Noda, M., Kadowaki, T.
(2002). Genetic Manipulations of Fatty Acid Metabolism in {beta}-Cells Are Associated With Dysregulated Insulin Secretion. Diabetes
51: S414-420
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Lay, S. L., Lefrere, I., Trautwein, C., Dugail, I., Krief, S.
(2002). Insulin and Sterol-regulatory Element-binding Protein-1c (SREBP-1C) Regulation of Gene Expression in 3T3-L1 Adipocytes. IDENTIFICATION OF CCAAT/ENHANCER-BINDING PROTEIN beta AS AN SREBP-1C TARGET. J. Biol. Chem.
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Ross, S. E., Erickson, R. L., Gerin, I., DeRose, P. M., Bajnok, L., Longo, K. A., Misek, D. E., Kuick, R., Hanash, S. M., Atkins, K. B., Andresen, S. M., Nebb, H. I., Madsen, L., Kristiansen, K., MacDougald, O. A.
(2002). Microarray Analyses during Adipogenesis: Understanding the Effects of Wnt Signaling on Adipogenesis and the Roles of Liver X Receptor {alpha} in Adipocyte Metabolism. Mol. Cell. Biol.
22: 5989-5999
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Halder, S. K., Fink, M., Waterman, M. R., Rozman, D.
(2002). A cAMP-Responsive Element Binding Site Is Essential for Sterol Regulation of the Human Lanosterol 14{alpha}-Demethylase Gene (CYP51). Mol. Endocrinol.
16: 1853-1863
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Andreolas, C., da Silva Xavier, G., Diraison, F., Zhao, C., Varadi, A., Lopez-Casillas, F., Ferre, P., Foufelle, F., Rutter, G. A.
(2002). Stimulation of Acetyl-CoA Carboxylase Gene Expression by Glucose Requires Insulin Release and Sterol Regulatory Element Binding Protein 1c in Pancreatic MIN6 {beta}-Cells. Diabetes
51: 2536-2545
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Ayala, J. E., Streeper, R. S., Svitek, C. A., Goldman, J. K., Oeser, J. K., O'Brien, R. M.
(2002). Accessory Elements, Flanking DNA Sequence, and Promoter Context Play Key Roles in Determining the Efficacy of Insulin and Phorbol Ester Signaling through the Malic Enzyme and Collagenase-1 AP-1 Motifs. J. Biol. Chem.
277: 27935-27944
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Roche, H. M., Noone, E., Sewter, C., Mc Bennett, S., Savage, D., Gibney, M. J., O'Rahilly, S., Vidal-Puig, A. J.
(2002). Isomer-Dependent Metabolic Effects of Conjugated Linoleic Acid: Insights From Molecular Markers Sterol Regulatory Element-Binding Protein-1c and LXR{alpha}. Diabetes
51: 2037-2044
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Flamez, D., Berger, V., Kruhoffer, M., Orntoft, T., Pipeleers, D., Schuit, F. C.
(2002). Critical Role for Cataplerosis via Citrate in Glucose-Regulated Insulin Release. Diabetes
51: 2018-2024
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Guillet-Deniau, I., Mieulet, V., Le Lay, S., Achouri, Y., Carre, D., Girard, J., Foufelle, F., Ferre, P.
(2002). Sterol Regulatory Element Binding Protein-1c Expression and Action in Rat Muscles: Insulin-Like Effects on the Control of Glycolytic and Lipogenic Enzymes and UCP3 Gene Expression. Diabetes
51: 1722-1728
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Yin, L., Zhang, Y., Hillgartner, F. B.
(2002). Sterol Regulatory Element-binding Protein-1 Interacts with the Nuclear Thyroid Hormone Receptor to Enhance Acetyl-CoA Carboxylase-alpha Transcription in Hepatocytes. J. Biol. Chem.
277: 19554-19565
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Moon, Y. S., Latasa, M.-J., Griffin, M. J., Sul, H. S.
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Lewis, G. F., Carpentier, A., Adeli, K., Giacca, A.
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Bartels, E. D., Lauritsen, M., Nielsen, L. B.
(2002). Hepatic Expression of Microsomal Triglyceride Transfer Protein and In Vivo Secretion of Triglyceride-Rich Lipoproteins Are Increased in Obese Diabetic Mice. Diabetes
51: 1233-1239
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Tobin, K. A. R., Ulven, S. M., Schuster, G. U., Steineger, H. H., Andresen, S. M., Gustafsson, J.-A., Nebb, H. I.
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277: 10691-10697
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Smih, F., Rouet, P., Lucas, S., Mairal, A., Sengenes, C., Lafontan, M., Vaulont, S., Casado, M., Langin, D.
(2002). Transcriptional Regulation of Adipocyte Hormone-Sensitive Lipase by Glucose. Diabetes
51: 293-300
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HORTON, J.D., GOLDSTEIN, J.L., BROWN, M.S.
(2002). SREBPs: Transcriptional Mediators of Lipid Homeostasis. Cold Spring Harb Symp Quant Biol
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Diraison, F., Dusserre, E., Vidal, H., Sothier, M., Beylot, M.
(2002). Increased hepatic lipogenesis but decreased expression of lipogenic gene in adipose tissue in human obesity. Am. J. Physiol. Endocrinol. Metab.
282: E46-E51
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Sone, H., Shimano, H., Sakakura, Y., Inoue, N., Amemiya-Kudo, M., Yahagi, N., Osawa, M., Suzuki, H., Yokoo, T., Takahashi, A., Iida, K., Toyoshima, H., Iwama, A., Yamada, N.
(2002). Acetyl-coenzyme A synthetase is a lipogenic enzyme controlled by SREBP-1 and energy status. Am. J. Physiol. Endocrinol. Metab.
282: E222-E230
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Elam, M. B., Wilcox, H. G., Cagen, L. M., Deng, X., Raghow, R., Kumar, P., Heimberg, M., Russell, J. C.
(2001). Increased hepatic VLDL secretion, lipogenesis, and SREBP-1 expression in the corpulent JCR:LA-cp rat. J. Lipid Res.
42: 2039-2048
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Becard, D., Hainault, I., Azzout-Marniche, D., Bertry-Coussot, L., Ferre, P., Foufelle, F.
(2001). Adenovirus-Mediated Overexpression of Sterol Regulatory Element Binding Protein-1c Mimics Insulin Effects on Hepatic Gene Expression and Glucose Homeostasis in Diabetic Mice. Diabetes
50: 2425-2430
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Tobe, K., Suzuki, R., Aoyama, M., Yamauchi, T., Kamon, J., Kubota, N., Terauchi, Y., Matsui, J., Akanuma, Y., Kimura, S., Tanaka, J., Abe, M., Ohsumi, J., Nagai, R., Kadowaki, T.
(2001). Increased Expression of the Sterol Regulatory Element-binding Protein-1 Gene in Insulin Receptor Substrate-2-/- Mouse Liver. J. Biol. Chem.
276: 38337-38340
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Heemers, H., Maes, B., Foufelle, F., Heyns, W., Verhoeven, G., Swinnen, J. V.
(2001). Androgens Stimulate Lipogenic Gene Expression in Prostate Cancer Cells by Activation of the Sterol Regulatory Element-Binding Protein Cleavage Activating Protein/Sterol Regulatory Element-Binding Protein Pathway. Mol. Endocrinol.
15: 1817-1828
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Escher, P., Braissant, O., Basu-Modak, S., Michalik, L., Wahli, W., Desvergne, B.
(2001). Rat PPARs: Quantitative Analysis in Adult Rat Tissues and Regulation in Fasting and Refeeding. Endocrinology
142: 4195-4202
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