Department of Biochemistry, School of Medicine, West Virginia University, Morgantown, West Virginia 26506
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ABSTRACT |
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Transcription of fatty acid synthase (FAS) and malic enzyme (ME) in avian liver is low during starvation or feeding a low-carbohydrate, high-fat diet and high during feeding a high-carbohydrate, low-fat diet. The role of glucose in the nutritional control of FAS and ME was investigated by determining the effects of this metabolic fuel on expression of FAS and ME in primary cultures of chick embryo hepatocytes. In the presence of triiodothyronine, glucose (25 mM) stimulated an increase in the activity and mRNA abundance of FAS and ME. These effects required the phosphorylation of glucose to glucose 6-phosphate but not further metabolism downstream of the aldolase step of the glycolytic pathway. Xylitol mimicked the effects of glucose on FAS and ME expression, suggesting that an intermediate of the pentose phosphate pathway may be involved in mediating this response. The effects of glucose on the mRNA abundance of FAS and ME were accompanied by similar changes in transcription of FAS and ME. These data support the hypothesis that glucose plays a role in mediating the effects of nutritional manipulation on transcription of FAS and ME in liver.
fatty acid synthesis; nutritional regulation; glucose signal; liver; thyroid hormone
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INTRODUCTION |
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IN BIRDS AND MAMMALS, one of the functions of the de novo synthesis of long-chain fatty acids is the provision of energy reserves during periods when dietary carbohydrate intake exceeds the immediate energy needs of the animal. Accordingly, rates of long-chain fatty acid synthesis in liver and adipose tissue are rapid during feeding a high-carbohydrate, low-fat diet, and slow during starvation or feeding a low-carbohydrate, high-fat diet (22, 49). Two enzymes that are involved in the synthesis of long-chain fatty acids are malic enzyme (ME, EC 1.1.1.40) and fatty acid synthase (FAS, EC 2.3.1.85). ME catalyzes the oxidative decarboxylation of malate to pyruvate and carbon dioxide, simultaneously generating NADPH from NADP+. FAS is a multifunctional polypeptide that catalyzes the synthesis of a molecule of palmitate from 1 molecule of acetyl- CoA, 7 molecules of malonyl-CoA, and 14 molecules of NADPH. The ME reaction supplies about 50% of the NADPH required for palmitate synthesis in rat liver and adipose tissue and nearly all of the NADPH needed for palmitate synthesis in chicken liver (9, 26, 36). The concentrations of FAS and ME in liver and adipose tissue are correlated with rates of fatty acid synthesis during different nutritional conditions. Thus the amount of FAS and ME is increased during feeding a high-carbohydrate, low-fat diet and decreased during starvation or feeding a low-carbohydrate, high-fat diet (6, 13, 17, 19, 27). Diet-induced changes in the concentrations of FAS and ME are mediated by alterations in the transcription rate of the respective genes (2, 5, 20, 31, 37). An understanding of the mechanisms controlling the transcription of FAS and ME is important because altered regulation of fatty acid synthesis is associated with several disease states such as obesity, diabetes, and atherosclerosis (22, 43).
Insulin, 3,5,3'-triiodothyronine (T3), and glucagon are widely considered to be humoral factors that communicate changes in nutritional status to the liver and other organs, thereby mediating the nutritional regulation of FAS and ME. This deduction is based on the observation that stimulation of transcription of FAS and ME caused by feeding a high-carbohydrate, low-fat diet is preceded or paralleled by increases in the molar ratio of insulin/glucagon and the levels of T3 in the blood (18, 22). A major role for insulin, T3, and glucagon is also indicated by the observation that these hormones regulate expression of lipogenic enzymes in various cell culture systems. For example, in primary cultures of chick embryo hepatocytes, T3 stimulates a 10- and 60-fold increase in transcription of FAS and ME, respectively (40, 47). Insulin accelerates the increase in transcription of FAS and ME caused by T3, whereas glucagon completely blocks the stimulatory effect of T3 on ME transcription.
Hormones may not be the only agents that participate in the nutritional regulation of FAS and ME. The level of glucose in the blood is also modulated by alterations in nutritional status. For example, the concentration of glucose in the blood is low in starved animals and high in animals fed a high-carbohydrate diet (22). Previous studies have shown that glucose stimulates an increase in the synthesis and mRNA abundance of FAS and ME in rat hepatocyte cultures (12, 32, 33, 38). Glucose also has been reported to cause an increase in FAS mRNA levels in rat white adipose tissue pieces (11) and the human hepatoma cell line Hep G2 (44). In experimental models of non-insulin-dependent diabetes mellitus, increased glucose flux across the liver is associated with elevated rates of fatty acid synthesis and increased expression of FAS (3, 45). Collectively, these findings suggest that glucose may serve as an extracellular signal in the control of lipogenic enzyme expression. In the present study, we investigated this possibility further by determining the effects of glucose on transcription of FAS and ME in chick embryo hepatocytes. We show that glucose increases the transcription of FAS and ME and that this effect is dependent on the presence of T3. We also provide data suggesting that an intermediate of the nonoxidative branch of the pentose phosphate pathway is involved in mediating the effects of glucose on expression of FAS and ME. Finally, based on comparison of the glucose response in chick embryo hepatocytes with that reported in rat hepatocytes and Hep G2 cells, we propose that fundamental differences exist between these cell culture systems in the mechanism by which glucose regulates expression of FAS and ME.
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MATERIALS AND METHODS |
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Chemicals.
Nucleotides (Pharmacia Biotechnology), proteinase K (Boehringer
Mannheim),
[-32P]UTP, and
[
-32P]dCTP (ICN
Biochemicals) were purchased from the indicated sources. Crystalline
bovine insulin was a gift from Lilly. All other chemicals were from
Sigma or of the highest purity commercially available.
Preparation and maintenance of isolated hepatocytes. Unincubated embryonated eggs from white Leghorn chickens were obtained from Truslow Farms (Chestertown, MD) and incubated in an electric forced draft incubator at 37.5 ± 0.5°C and 80% relative humidity. Embryos (19 days of age) were killed by decapitation, the livers were removed, and hepatocytes were isolated (15). The isolated hepatocytes were incubated in Waymouth's medium MD705/1 (GIBCO) containing penicillin (60 µg/ml) and streptomycin (100 µg/ml) on untreated plastic petri dishes (Fisher) at 40°C in a humidified atmosphere of 5% CO2 and 95% air. One 90-mm petri dish contained 1 ml of cell suspension (2-3 mg total protein, ~1 × 107 cells) and 9 ml of medium. The medium on all plates was changed after about 18 h of incubation. Hormone and other additions were as described in the legends to the figures and table. Because T3 is rapidly degraded in serum-free Waymouth's medium (19), high concentrations of T3 (1.6 µM) were employed in long-term incubations to ensure that optimal levels of T3 were present throughout the incubation. FAS (15), ME (50), and protein (42) were assayed by the indicated methods.
Isolation of RNA and quantitation of mRNA levels. Medium was removed and RNA was extracted from cells by the guanidinium thiocyanate-phenol-chloroform method (4). Total RNA (15 µg) was separated by size in 0.9% agarose, 0.7 M formaldehyde gels, and then transferred to a Nytran membrane (Schleicher & Schuell) using a vacuum blotting apparatus (Pharmacia Biotechnology). The RNA was crosslinked to the membrane by ultraviolet and baked at 80°C for 30-60 min. RNA blots were hybridized with 32P-labeled DNA probes labeled by random priming (8). Hybridization and washes were as described (1). Membranes were subjected to storage phosphor autoradiography. Hybridization signals were quantified using ImageQuant software (Molecular Dynamics).
Nuclear run-on assay of transcription rates.
Nuclei were isolated from the pooled cells of fifteen 90-mm plates (40,
41). Approximately 5 × 107
nuclei were stored at 80°C in 100-µl aliquots containing
50 mM
N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic
acid, pH 7.4, 75 mM NaCl, 0.1 mM EDTA, 5 mM dithiothreitol, 0.125 mM
phenylmethylsulfonyl fluoride, and 50% glycerol. The in vitro
elongation reactions were carried out as described (14, 20).
32P-labeled RNA transcripts were
purified by the method of Linial et al. (29), using NICK columns
(Pharmacia Biotechnology) as described in the manufacturer's
instructions. Denaturation of DNA probes, application of DNA to
GeneScreen membranes, hybridization of
32P-labeled RNA transcripts to
membrane-bound DNA, and posthybridization washes were carried out as
described (20). Hybridization signals were quantified as previously
described.
DNA probes.
Chicken cDNAs for FAS, glyceraldehyde-3-phosphate dehydrogenase, and
-actin were generously provided by Drs. Gordon G. Hammes (Duke
University), Robert Schwartz (Baylor College of Medicine), and Don W. Cleveland (Johns Hopkins University), respectively. These DNAs were
used as probes in both Northern and nuclear run-on analyses. The
chicken cDNA for ME was provided by Dr. Alan G. Goodridge (Ohio State
University) and was used as a probe in Northern analysis. The chicken
ME genomic DNA, ME-4.8-5', has been described (31, 40) and
was used as a probe in nuclear run-on assays.
Statistics. Data were subjected to analysis of variance, and statistical comparisons were made with Dunnett's test or Student's t-test. Statistical significance is defined as P < 0.05.
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RESULTS |
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Glucose stimulates expression of FAS and ME in chick embryo hepatocytes. The ability of glucose to regulate the expression of FAS and ME in avian liver was investigated by determining the effects of different concentrations of glucose on the activities and mRNA levels for FAS and ME in primary cultures of chick embryo hepatocytes incubated in the absence or presence of insulin, T3, or insulin plus T3. Incubation of hepatocytes with T3 in the presence of 2.5 mM glucose stimulated a 2.3- and 42.6-fold increase in the activities of FAS and ME, respectively (Table 1). An increase in the glucose concentration in the culture medium to 25 mM amplified the T3-induced increase in FAS and ME activity by 3.1- and 1.5-fold, respectively. Glucose (25 mM) caused a similar stimulation in the activities of FAS and ME in hepatocytes incubated with insulin plus T3. Addition of glucose by itself or in combination with insulin had no effect on the activities of FAS or ME. Thus glucose increases the activities of ME and FAS in avian hepatocytes, and this effect requires the presence of T3.
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Role of intermediates of glycolytic pathway and pentose phosphate pathway in mediating effects of glucose on expression of FAS and ME. To assess the specificity of the action of glucose and to determine whether the effects of glucose on expression of FAS and ME are mediated by glucose per se or by specific intermediates of the glycolytic pathway, we investigated the ability of various metabolic fuels and nonmetabolizable analogs of glucose to stimulate the accumulation of mRNA for FAS and ME in the presence of T3. In hepatocytes incubated with 5 mM dihydroxyacetone or 10 mM lactate and 1 mM pyruvate, the accumulation of mRNA for FAS and ME was similar to that of cells incubated with 0 mM glucose (Fig. 2). Addition of dihydroxyacetone or lactate and pyruvate had no effect on the abundance of mRNA for FAS and ME in the absence of T3 (data not shown). These results indicate that metabolism downstream of the aldolase step in the glycolytic pathway is not sufficient for the glucose-induced increase in the abundance of mRNA for FAS and ME.
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Role of transcription in mediating effects of glucose on abundance
of mRNA for FAS and ME.
We next determined whether the effects of glucose on the abundance of
mRNA for FAS and ME were due to changes in gene transcription. Nuclear
run-on assays were performed using nuclei prepared from hepatocytes
treated with or without T3 in the
presence of 2.5 mM glucose or 25 mM glucose. In hepatocytes incubated
with T3 and 25 mM glucose,
transcription of FAS and ME was increased by 3.8- and 1.8-fold,
respectively, relative to cells incubated with T3 and 2.5 mM glucose (Fig.
4). Glucose had no effect on transcription of FAS and ME in hepatocytes incubated without
T3. These changes in the
transcription of FAS and ME were comparable to alterations in
accumulation of the respective mRNAs for these genes (Fig. 1),
indicating that the effects of glucose are mediated primarily by a
transcriptional mechanism. The effects of glucose on transcription of
FAS and ME were specific because transcription of the genes for
glyceraldehyde-3-phosphate dehydrogenase and -actin were not
affected by alterations in the concentration of glucose in the culture
medium (Fig. 4).
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DISCUSSION |
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Previous work investigating the regulation of FAS and ME in chick embryo hepatocytes has focused on the ability of hormones to control the expression of these enzymes. In this report, we demonstrate that the important dietary substrate glucose also regulates expression of FAS and ME in avian hepatocytes. Our results indicate that glucose stimulates an increase in expression of FAS and ME and that this effect is manifested only in the presence of T3 (Table 1 and Figs. 1 and 4). The finding that T3 is required for glucose responsiveness in chick embryo hepatocytes contrasts with the results of previous studies examining the effects of glucose on lipogenic enzyme expression in rat hepatocytes and white adipose tissue pieces and in the human hepatoma cell line Hep G2. In rat hepatocytes, glucose is effective in stimulating expression of FAS and ME in the absence of T3 (12, 32, 33, 38). Stimulation of FAS expression by glucose in Hep G2 cells and rat white adipose tissue pieces is also not dependent on the presence of T3 (11, 44). Thus, in avian hepatocytes, glucose regulates the expression of FAS and ME by modulating the activity of the T3 signaling pathway, whereas in Hep G2 cells and rat hepatocytes and adipocytes, a different mechanism appears to be involved in mediating the effects of glucose on expression of lipogenic enzymes. The reason for these differences in the mechanism of action of glucose is presently unclear.
Another interesting characteristic of the glucose-induced increase in expression of FAS and ME in chick embryo hepatocytes is that it does not require the presence of insulin (Table 1). This observation contrasts with the results of previous studies in rat hepatocytes demonstrating that the stimulatory effects of glucose on expression of FAS and ME require the presence of insulin (12, 32, 33, 38). Differences between chick hepatocytes and rat hepatocytes in the requirement for insulin for glucose responsiveness may be due to differences in the properties of hexokinases that catalyze the phosphorylation of glucose to glucose 6-phosphate. In rat hepatocytes, hexokinase activity is dependent on the presence of insulin (23), whereas, in chicken hepatocytes, hexokinase activity is not dependent on the presence of insulin (28, 46). As in chick embryo hepatocytes, the effect of glucose on FAS expression in Hep G2 cells does not require the presence of insulin (44). Thus hexokinase activity in Hep G2 cells is probably insulin independent.
Two different signaling pathways have been suggested to play a role in mediating the effects of glucose on lipogenic enzyme expression in rat hepatocytes. Girard and co-workers (10, 13) have postulated that the proximal signal mediating the effects of glucose on FAS expression is glucose 6-phosphate. This proposal is based on the observations that 2-deoxyglucose is effective in mimicking the effects of glucose on FAS mRNA levels and that glucose-induced alterations in FAS mRNA abundance are positively correlated with changes in intracellular glucose 6-phosphate levels. Mariash and Oppenheimer (32) have suggested that another signaling pathway is involved in mediating the effects of glucose on ME expression in rat hepatocytes. They have proposed that the proximal signal mediating the glucose-induced increase in ME expression arises at the level of mitochondrial oxidation of pyruvate. This proposal is based on the observations that any carbohydrate intermediate entering the glycolytic pathway at or above pyruvate is effective in stimulating ME activity and that dichloroacetic acid, a stimulator of pyruvate dehydrogenase, is able to increase ME activity in the absence of insulin or the presence of glucagon. Interestingly, our results in chick embryo hepatocytes suggest that neither glucose 6-phosphate nor a metabolite distal of the aldolase step of the glycolytic pathway is involved in mediating the effects of glucose on expression of FAS and ME. 2-Deoxyglucose, dihydroxyacetone, and lactate plus pyruvate were not effective in stimulating FAS and ME mRNA levels in chick embryo hepatocytes (Fig. 2). A lack of a role for glucose 6-phosphate in mediating glucose-induced changes in lipogenic enzyme expression in chick embryo hepatocytes is supported by the observation that expression of acetyl-CoA carboxylase in these cells is not closely correlated with intracellular levels of glucose 6-phosphate (21). Thus our findings provide further support for the proposal that the mechanism mediating the effects of glucose on expression of FAS and ME in chick hepatocytes is fundamentally different from that in rat hepatocytes.
Intermediates of the nonoxidative branch of the pentose phosphate pathway have also been proposed to mediate the effects of glucose on gene expression. This hypothesis is based on the observation that glucose treatment increases xylulose 5-phosphate levels in perfused liver (30), and that low concentrations of xylitol are effective in mimicking the stimulatory effects of glucose on L-pyruvate kinase transcription in mhAT3-F hepatoma cells without altering intracellular glucose 6-phosphate levels (7). Our finding that xylitol is effective in stimulating the accumulation of mRNA for FAS and ME in chick embryo hepatocytes (Fig. 3) is consistent with xylulose 5-phosphate or another intermediate of the pentose phosphate pathway playing a role in regulating the expression of these enzymes.
Recently, Mourrieras et al. (34) have reported that stimulation of FAS and S14 mRNA levels by glucose and xylitol in rat hepatocyte cultures is more closely correlated with changes in intracellular glucose 6-phosphate levels than xylulose 5-phosphate levels, supporting the hypothesis that glucose 6-phosphate is involved in the regulation of lipogenic enzyme expression. These observations contrast with the findings of Doiron et al. (7) demonstrating that stimulation of L-pyruvate kinase transcription by xylitol in mhAT3-F cells is not associated with changes in intracellular glucose 6-phosphate levels and data from our laboratory (21) demonstrating that stimulation of acetyl-CoA carboxylase expression by glucose in chick embryo hepatocytes is not closely correlated with glucose 6-phosphate levels. One explanation for the contradictory observations is that the effects of glucose and xylitol on lipogenic enzyme expression are mediated by different metabolic intermediates in different cell types. Another possibility is that neither glucose 6-phosphate nor xylulose 5-phosphate is involved in mediating these responses and that another unidentified metabolic intermediate functions in the transduction of the glucose signal. Resolution of these discrepant findings will require additional analyses that directly define the metabolites involved in the regulation of lipogenic enzyme expression by glucose. One such approach is to trace the intracellular pathway for glucose from the target sequences in lipogenic genes to the active metabolite. Experiments are in progress aimed at characterizing the cis-acting elements that mediate the effects of glucose on lipogenic gene transcription in chick embryo hepatocytes.
Another significant finding of the present study is that transcription is the primary process through which glucose increases expression of FAS and ME in chick embryo hepatocytes (Fig. 4). This finding supports the hypothesis that glucose plays a role in mediating the effects of nutritional manipulation on transcription of FAS and ME in liver. Our data demonstrating that glucose acts through a transcriptional mechanism to regulate FAS expression in chick embryo hepatocytes contrast with the results of a previous report (44) examining the effects of glucose on FAS expression in Hep G2 cells. In the latter cell line, the stimulatory effect of glucose on abundance of FAS mRNA is due largely to changes in the stability of this mRNA. The reason for the discrepant results between the chicken and human systems is unclear. One possibility is that chickens and humans have evolved different mechanisms for the regulation of expression of lipogenic enzymes by glucose. Alternatively, differences in the mechanism of glucose action between chick embryo hepatocytes and Hep G2 cells may be due to the transformed nature of the latter cell line.
The effects of starvation and refeeding a high-carbohydrate, low-fat diet on transcription of FAS and ME are mimicked quantitatively in primary cultures of chick embryo hepatocytes by manipulating the concentrations of T3, insulin, glucagon, and glucose in the culture medium (Fig. 4) (40, 47). Thus this cell culture system appears to be a good model for the regulation of FAS and ME in livers of intact chickens. For similar reasons, primary cultures of rodent hepatocytes also appear to be a good model for the regulation of lipogenic enzymes in livers of intact rats (12, 32, 33, 38). Because the mechanism by which glucose regulates FAS and ME in chick embryo hepatocytes appears to be different from that in rat hepatocytes, class-specific differences may exist in the mechanism by which dietary carbohydrate regulates lipogenic enzyme transcription in vivo.
Because the effects of glucose on transcription of FAS and ME in chick embryo hepatocytes are dependent on the presence of T3, we postulate that a metabolite(s) of glucose enhances the ability of the liganded form of the nuclear T3 receptor to stimulate the transcription of these genes. How can this metabolite increase the transcriptional activity of the nuclear T3 receptor? One possibility is that the metabolite directly binds to the nuclear T3 receptor and regulates its function or interacts with a nuclear protein that modulates the transcriptional activity of the nuclear T3 receptor. For example, a metabolite of glucose may be a ligand for an as yet to be described orphan receptor that dimerizes with the nuclear T3 receptor. Another possibility is that a metabolite of glucose triggers a phosphorylation-dephosphorylation cascade, resulting in an alteration in the phosphorylation state of the nuclear T3 receptor or a protein that modulates the activity of the nuclear T3 receptor. Protein phosphorylation is thought to play a role in regulating T3 action because protein kinase inhibitors inhibit and protein phosphatase inhibitors enhance the effects of T3 on gene transcription (25, 48). Elucidation of the molecular mechanisms by which glucose regulates transcription of FAS and ME in hepatocytes may lead to new insights on how metabolic intermediates regulate gene expression in higher eucaryotes.
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ACKNOWLEDGEMENTS |
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This work was supported by the American Heart Association, West Virginia Affiliate.
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FOOTNOTES |
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Address for reprint requests: F. B. Hillgartner, Dept. of Biochemistry, PO Box 9142, West Virginia Univ., Morgantown, WV 26506-9142.
Received 12 September 1997; accepted in final form 25 November 1997.
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REFERENCES |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
1.
Amasino, R. M.
Acceleration of nucleic acid hybridization rate by polyethylene glycol.
Anal. Biochem.
162:
304-307,
1986.
2.
Back, D. W.,
M. J. Goldman,
J. E. Fisch,
R. S. Ochs,
and
A. G. Goodridge.
The fatty acid synthase gene in avian liver: two mRNAs are expressed and regulated in parallel by feeding, primarily at the level of transcription.
J. Biol. Chem.
261:
4190-4197,
1986
3.
Bazin, R.,
and
M. Lavau.
Development of hepatic and adipose tissue lipogenic enzymes and insulinemia during suckling and weaning on to a high-fat diet in Zucker rats.
J. Lipid Res.
23:
839-849,
1982
4.
Chomczynski, P.,
and
N. Sacchi.
Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction.
Anal. Biochem.
162:
156-159,
1987[Medline].
5.
Cochary, E. F.,
Z. Kikinis,
and
K. E. Paulson.
Positional and temporal regulation of lipogenic gene expression in mouse liver.
Gene Expr.
3:
265-278,
1993[Medline].
6.
Craig, M. C.,
C. M. Nepokroeff,
M. R. Lakshmanan,
and
J. W. Porter.
Effect of dietary change on the rates of synthesis and degradation of rat liver fatty acid synthetase.
Arch. Biochem. Biophys.
152:
619-630,
1972[Medline].
7.
Doiron, B.,
M.-H. Cuif,
R. Chen,
and
A. Kahn.
Transcriptional glucose signaling through the glucose response element is mediated by the pentose phosphate pathway.
J. Biol. Chem.
271:
5321-5324,
1996
8.
Feinberg, A. P.,
and
B. Vogelstein.
A technique for radiolabeling DNA restriction endonuclease fragments to high specific activity.
Anal. Biochem.
132:
6-13,
1983[Medline].
9.
Flatt, J. P.,
and
E. G. Ball.
Studies on the metabolism of adipose tissue. XV. An evaluation of the major pathways of glucose catabolism as influenced by insulin and epinephrine.
J. Biol. Chem.
239:
675-685,
1964
10.
Foufelle, F.,
J. Girard,
and
P. Ferre.
Regulation of lipogenic enzyme expression by glucose in liver and adipose tissue: is glucose 6-phosphate the signalling metabolite?
Biochem. Soc. Trans.
24:
372-378,
1996[Medline].
11.
Foufelle, F.,
B. Gouhot,
J.-P. Pegorier,
D. Perdereau,
J. Girard,
and
P. Ferre.
Glucose stimulation of lipogenic enzyme gene expression in cultured white adipose tissue.
J. Biol. Chem.
267:
20543-20546,
1992
12.
Gifforn-Katz, S.,
and
N. R. Katz.
Carbohydrate-dependent induction of fatty acid synthase in primary cultures of rat hepatocytes.
Eur. J. Biochem.
159:
513-518,
1986[Abstract].
13.
Girard, J.,
D. Perdereau,
F. Foufelle,
C. Prip-Buus,
and
P. Ferre.
Regulation of lipogenic enzyme gene expression by nutrients and hormones.
FASEB J.
8:
36-42,
1994
14.
Goldman, M. J.,
D. W. Back,
and
A. G. Goodridge.
Nutritional regulation of the synthesis and degradation of malic enzyme messenger RNA in duck liver.
J. Biol. Chem.
260:
4404-4408,
1985[Abstract].
15.
Goodridge, A. G.
Regulation of the activity of acetyl coenzyme A carboxylase by palmitoyl coenzyme A and citrate.
J. Biol. Chem.
247:
6946-6952,
1972
16.
Goodridge, A. G.
Regulation of fatty acid synthesis in isolated hepatocytes prepared from livers of neonatal chicks.
J. Biol. Chem.
248:
1924-1931,
1973
17.
Goodridge, A. G.
Regulation of the gene for fatty acid synthase.
Federation Proc.
45:
2399-2405,
1986[Medline].
18.
Goodridge, A. G.,
D. W. Back,
S. B. Wilson,
and
M. J. Goldman.
Regulation of genes for enzymes involved in fatty acid synthesis.
Ann. NY Acad. Sci.
478:
46-62,
1986[Abstract].
19.
Goodridge, A. G.,
S. A. Klautky,
D. A. Fantozzi,
R. A. Baillie,
D. W. Hodnett,
W. Chen,
D. C. Thurmond,
G. Xu,
and
C. Roncero.
Nutritional and hormonal regulation of expression of the gene for malic enzyme.
In: Progress in Nucleic Acid Research and Molecular Biology, edited by W. E. Cohn,
and K. Moldave. San Diego, CA: Academic, 1996, vol. 52, p. 89-121.
20.
Hillgartner, F. B.,
T. Charron,
and
K. A. Chesnut.
Alterations in nutritional status regulate acetyl-CoA carboxylase expression in avian liver by a transcriptional mechanism.
Biochem. J.
319:
263-268,
1996[Medline].
21.
Hillgartner, F. B.,
T. Charron,
and
K. A. Chesnut.
Triiodothyronine stimulates and glucagon inhibits transcription of the acetyl-CoA carboxylase gene in chick embryo hepatocytes. Glucose and insulin amplify the effect of triiodothyronine.
Arch. Biochem. Biophys.
337:
159-168,
1997[Medline].
22.
Hillgartner, F. B.,
L. M. Salati,
and
A. G. Goodridge.
Physiological and molecular mechanisms involved in nutritional regulation of fatty acid synthesis.
Physiol. Rev.
75:
47-76,
1995
23.
Iynedjian, P. B.,
D. Jotterand,
T. Nouspikel,
M. Asfari,
and
P.-R. Pilot.
Transcriptional induction of glucokinase gene by insulin in cultured liver cells and its repression by the glucagon-cAMP system.
J. Biol. Chem.
264:
21824-21829,
1989
24.
Jenkins, A. B.,
S. M. Furler,
and
E. W. Kraegen.
2-Deoxy-6-glucose metabolism in individual tissues of the rat in vivo.
Int. J. Biochem.
18:
311-318,
1986[Medline].
25.
Jones, K. E.,
J. H. Brubaker,
and
W. W. Chin.
Evidence that phosphorylation events participate in thyroid hormone action.
Endocrinology
134:
543-548,
1994[Abstract].
26.
Katz, J.,
and
R. Rognstad.
The metabolism of tritiated glucose by rat adipose tissue.
J. Biol. Chem.
241:
3600-3610,
1966
27.
Kim, T.-S.,
and
H. C. Freake.
High carbohydrate diet and starvation regulate lipogenic mRNA in rats in a tissue-specific manner.
J. Nutr.
126:
611-617,
1996[Medline].
28.
Klandorf, H.,
B. L. Clarke,
A. C. Scheck,
and
J. Brown.
Regulation of glucokinase activity in the domestic fowl.
Biochem. Biophys. Res. Commun.
139:
1086-1093,
1986[Medline].
29.
Linial, M.,
N. Gunderson,
and
M. Groudine.
Enhanced transcription of c-myc in bursal lymphoma cells requires continuous protein synthesis.
Science
230:
1126-1132,
1985[Medline].
30.
Liu, Y. Q.,
and
K. Uyeda.
A mechanism for fatty acid inhibition of glucose utilization in liver. Role of xylulose 5-P.
J. Biol. Chem.
271:
8824-8830,
1996
31.
Ma, X.-J.,
L. M. Salati,
S. E. Ash,
D. A. Mitchell,
S. A. Klautky,
D. A. Fantozzi,
and
A. G. Goodridge.
Nutritional regulation and tissue-specific expression of the malic enzyme gene in the chicken. Transcriptional control and chromatin structure.
J. Biol. Chem.
265:
18435-18441,
1990
32.
Mariash, C. N.,
and
J. H. Oppenheimer.
Stimulation of malic enzyme formation in hepatocyte culture by metabolites: evidence favoring a nonglycolytic metabolite as the proximate induction signal.
Metabolism
33:
545-552,
1983.
33.
Molero, C.,
M. Benito,
and
M. Lorenzo.
Regulation of malic enzyme gene expression by nutrients, hormones, and growth factors in fetal hepatocyte primary cultures.
J. Cell. Physiol.
155:
197-203,
1993[Medline].
34.
Mourrieras, F.,
F. Foufelle,
M. Foretz,
J. Morin,
S. Bouche,
and
P. Ferre.
Induction of fatty acid synthase and S14 gene expression by glucose, xylitol and dihydroxyacetone in cultured rat hepatocytes is closely correlated with glucose 6-phosphate concentrations.
Biochem. J.
326:
345-349,
1997[Medline].
35.
Nishimura, M.,
and
K. Uyeda.
Purification and characterization of a novel xylulose 5-phosphate-activated protein phosphatase catalyzing dephosphorylation of fructose-6-phosphate, 2-kinase: fructose-2, 6-bisphosphatase.
J. Biol. Chem.
270:
26341-26346,
1995
36.
O'Hea, E. K.,
and
G. A. Leveille.
Lipogenesis in isolated adipose tissue of the domestic chick (Gallus Domesticus).
Comp. Biochem. Physiol. A Physiol.
26:
111-120,
1968.
37.
Paulauskis, J. D.,
and
H. S. Sul.
Hormonal regulation of mouse fatty acid synthase gene transcription in liver.
J. Biol. Chem.
264:
574-577,
1989
38.
Prip-Buus, C.,
D. Perdereau,
F. Foufelle,
J. Maury,
P. Ferre,
and
J. Girard.
Induction of fatty-acid-synthase gene expression by glucose in primary culture of rat hepatocytes. Dependency upon glucokinase activity.
Eur. J. Biochem.
230:
309-315,
1995[Abstract].
39.
Salas, J.,
M. Salas,
E. Vinuela,
and
A. Sols.
Glucokinase of rabbit liver. Purification and properties.
J. Biol. Chem.
240:
1014-1018,
1965
40.
Salati, L. M.,
X.-J. Ma,
C. C. McCormick,
S. R. Stapleton,
and
A. G. Goodridge.
Triiodothyronine stimulates and cyclic AMP inhibits transcription of the gene for malic enzyme in chick embryo hepatocytes in culture.
J. Biol. Chem.
266:
4010-4016,
1991
41.
Schibler, U.,
O. Hagenbuchle,
P. K. Wellauer,
and
A. C. Pittet.
Two promoters of different strengths control the transcription of the mouse alpha-amylase gene Amy-1 in the parotid gland and the liver.
Cell
33:
501-508,
1983[Medline].
42.
Sedmak, J. J.,
and
S. E. Grossberg.
A rapid, sensitive, and versatile assay for protein using Coomassie brilliant blue G250.
Anal. Biochem.
79:
544-552,
1977[Medline].
43.
Semenkovich, C. F.
Regulation of fatty acid synthase.
Prog. Lipid Res.
36:
43-53,
1997[Medline].
44.
Semenkovich, C. F.,
T. Coleman,
and
R. Goforth.
Physiologic concentrations of glucose regulate fatty acid synthase activity in Hep G2 cells by mediating fatty acid synthase mRNA stability.
J. Biol. Chem.
268:
6961-6970,
1993
45.
Shillabeer, G.,
J. Hornford,
J. M. Forden,
N. C. Wong,
J. C. Russell,
and
C. Lau.
Fatty acid synthase and adipsin mRNA levels in obese and lean JCR: LA-cp rats: effect of diet.
J. Lipid Res.
33:
31-39,
1992[Abstract].
46.
Stanley, J. C.,
G. L. Dohm,
B. S. McManus,
and
E. A. Newsholme.
Activities of glucokinase and hexokinase in mammalian and avian livers.
Biochem. J.
224:
667-671,
1984[Medline].
47.
Stapleton, S. R.,
D. A. Mitchell,
L. M. Salati,
and
A. G. Goodridge.
Triiodothyronine stimulates transcription of the fatty acid synthase gene in chick embryo hepatocytes in culture. Insulin and insulin-like growth factor amplify that effect.
J. Biol. Chem.
265:
18442-18446,
1990
48.
Swierczynski, J.,
D. A. Mitchell,
D. S. Reinhold,
L. M. Salati,
S. R. Stapleton,
S. A. Klautky,
A. E. Struve,
and
A. G. Goodridge.
Triiodothyronine-induced accumulations of malic enzyme, fatty acid synthase, acetyl-coenzyme A carboxylase, and their mRNAs are blocked by protein kinase inhibitors.
J. Biol. Chem.
266:
17459-17466,
1991
49.
Wakil, S. J.,
J. K. Stoops,
and
V. C. Joshi.
Fatty acid synthesis and its regulation.
Annu. Rev. Biochem.
52:
537-579,
1983[Medline].
50.
Wise, E. M.,
and
E. G. Ball.
Malic enzyme and lipogenesis.
Proc. Natl. Acad. Sci. USA
52:
1255-1263,
1964[Medline].
51.
Woods, H. F.,
and
H. A. Krebs.
Xylitol metabolism in the isolated perfused rat liver.
Biochem. J.
134:
437-443,
1973.