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© 2007 The American Society for Nutrition J. Nutr. 137:554-559, March 2007

Biochemical, Molecular, and Genetic Mechanisms

Several Transcription Factors Are Recruited to the Glucose-6-Phosphatase Gene Promoter in Response to Palmitate in Rat Hepatocytes and H4IIE Cells1

Chuan Xu2, Kaushik Chakravarty3, Xiaoying Kong3, Tertius T. Tuy3, Ifeanyi J. Arinze5, Frederic Bone4 and Duna Massillon2,*

Departments of 2 Nutrition, 3 Biochemistry, and 4 Physiology-Biophysics, Case Western Reserve University School of Medicine, Cleveland, OH, 44106-4935 and the 5 Department of Biomedical Sciences, Meharry Medical College, Nashville, TN 37208-3599

* To whom correspondence should be addressed. E-mail: duna.massillon{at}case.edu.


   ABSTRACT
TOP
 ABSTRACT
Introduction
 Materials and Methods
 Results
 Discussion
 LITERATURE CITED
 
Fatty acids and glucose are strong modulators of the expression of glucose-6-phosphatase (Glc-6-Pase), an enzyme that plays a key role in glucose homeostasis. PUFA inhibit, whereas SFA and monounsaturated fatty acids induce the expression of the Glc-6-Pase gene. Palmitate and oleate are the most abundant fatty acid species in circulation during food deprivation in mammals. Although dietary fats have been shown to modulate the expression of genes involved in both lipid and carbohydrate metabolism in liver, little is known regarding the molecular mechanism of transcriptional response of the Glc-6-Pase gene to long-chain fatty acids. Using H4IIE hepatoma cells and hepatocytes from adult rats, we investigated the mechanism of the induction of this gene by palmitate and oleate. Both of these fatty acids stimulated Glc-6-Pase gene transcription but did not affect the stability of its mRNA. In transient transfection assays, transcription from the Glc-6-Pase gene promoter was markedly enhanced by both palmitate and oleate but not by arachidonate. Chromatin immunoprecipitation analysis was used to show that palmitate induced the recruitment of an array of transcription factors viz hepatic nuclear factor(NF)-4{alpha}, CAAT/enhancer binding proteinß, PPAR{alpha}, chicken ovalbumin upstream promoter transcription factor (COUP-TF), cAMP regulatory element binding protein, and NF-{kappa}B to this gene promoter. Although it is presently unclear how these various transcription factors interact at this promoter, the data are consistent with the view that multiple regulatory elements in the Glc-6-Pase gene promoter are responsible for the modulation of gene transcription by fatty acids.


   Introduction
TOP
 ABSTRACT
 Introduction
Materials and Methods
 Results
 Discussion
 LITERATURE CITED
 
Glucose-6-phosphatase (Glc-6-Pase)6, a multicomponent enzyme complex located in the endoplasmic reticulum of liver, kidney, and the small intestine, plays a critical role in glucose homeostasis. Transcription from the Glc-6-Pase gene promoter responds exquisitely to catabolic as well as anabolic hormones. For example, glucagon and glucocorticoids up-regulate the expression and activity of the catalytic unit (1–4), whereas high insulin levels rapidly suppress transcription of the gene (5–7). In addition to hormonal regulation, the activity and expression of the catalytic unit are also regulated by metabolites, specifically glucose and fatty acids (3,6,8).

Different classes of fatty acids seem to have differential effects on Glc-6-Pase expression and/or activity. Short-chain and long-chain SFA increase Glc-6-Pase promoter activity, whereas PUFA decrease its activity (9,10) as well as transcription from its gene promoter (11). Palmitate (a saturated long-chain fatty acid) and oleate (a monounsaturated fatty acid) are the most abundant fatty acid species in circulation in food-deprived mammals. Their circulating levels are high during starvation and low following refeeding a high-carbohydrate meal. Although changes in their circulating levels mimic hepatic Glc-6-Pase activity and although dietary fats have been shown to significantly modulate the expression of genes involved in both lipid and carbohydrate metabolism in liver, little is known regarding molecular mechanism of transcriptional response of the Glc-6-Pase gene to long-chain fatty acids (11).

Using isolated rat hepatocytes and the H4IIE hepatoma cell line, we have investigated the molecular mechanism(s) by which palmitate and oleate regulate the expression of the gene for the catalytic subunit of the Glc-6-Pase enzyme complex.


   Materials and Methods
TOP
 ABSTRACT
 Introduction
 Materials and Methods
Results
 Discussion
 LITERATURE CITED
 
    Cell culture and transfection. Hepatocytes were isolated from male Sprague-Dawley rats (Charles River Laboratories) that were food deprived overnight and used to establish primary cultures, as previously described (12). Rats aged 6–8 wk were used for all studies. Prior to withdrawal of food, the rats consumed a commercial diet (LabDiet 5P00, 22% protein, 5% fat, and 5% crude fiber) ad libitum and had free access to water at all times. All rats were cared for in the animal care facility of Case Western Reserve University in accordance with a protocol approved by the Institutional Animal Care and Use Committee. The hepatoma cell line H4IIE cells were grown in culture, as previously described (12). H4IIE cells were transfected with the –402/66 fragment of the Glc-6-Pase gene promoter linked to the luciferase reporter gene (this construct is designated as –402/+66-LUC). For transfection studies, promoter activity was normalized to the protein content of the samples.

    RNA isolation and northern-blotting analysis. Total RNA was isolated from primary cultures of hepatocytes (6 x 106 cells per plate) using TRIzol Reagent (Invitrogen); northern-blotting analyses were performed, as described previously (12).

    Fatty acid solutions. Each fatty acid was dissolved in a 1:1 ethanol:water (v:v) solution at 50°C (13) to make a stock concentration of 100 mmol/L. Aliquots of stock solutions were complexed with fatty acid-free bovine serum albumin (10% solution in water) by stirring for 1 h at 37°C and then diluted in culture media. For the controls, a solution of the vehicle (ethanol:water) mixed with fatty acid-free bovine serum albumin (10% solution in water) was used.

    Expression plasmids. Expression plasmids harboring genes for hepatic nuclear factor (HNF)-4{alpha} were obtained from Dr. Todd Leff (University of Michigan, Ann Arbor, MI). Expression plasmid for PPAR coactivator 1{alpha} (PGC-1{alpha}) was provided by Dr. Bruce Spiegelman (Dana Farber Cancer Institute, Boston MA). The cDNA for Glc-6-Pase was obtained from Dr. Rebecca Taub (University of Pennsylvania, Philadelphia, PA) and that for glucose-6-phosphate translocase (G6PT) was obtained by PCR amplification, as previously described (12).

    Chromatin immunoprecipitation assays. Chromatin immunoprecipitation (ChIP) assay was performed using hepatocytes in 100-mm dishes, as previously described (12). The following primer sets were used to analyze binding to the target regions: region 1 (–209/+9), 5'-CACTTCCGGCAGTAGCAAAC (forward) and 5'-ACAGCCTGATCGCCATTG (reverse); region 2 (–395/–185), 5'-GCTCTGCCAATGGCGATCAG-3' (forward) and 5'-CCCTCTGCTATCAGTCTGTGCC-3' (reverse). The PCR cycle was 95°C for 30 s, 65°C for 1 min, and 72°C for 2 min. Following 30 cycles of amplification, the PCR products were separated by electrophoresis on a 1.5% agarose gel and visualized by ethidium bromide staining.

    Statistics. Results are expressed as means ± SEM. Treatment differences were determined either by ANOVA followed by Fisher's multiple comparison test, or by nonparametric statistical method using Mann-Whitney U test. Significance is defined as P < 0.05.


   Results
TOP
 ABSTRACT
 Introduction
 Materials and Methods
 Results
Discussion
 LITERATURE CITED
 
    Glc-6-Pase mRNA level increased by saturated and monounsaturated fatty acids. Incubation of primary cultures of rat hepatocytes with palmitate or oleate for 2 h resulted in an increase in Glc-6-Pase mRNA (Fig. 1). With oleate, the effect was maximal at ~50 µmol/L (Fig. 1A); with palmitate, increases occurred even up to 100 µmol/L (Fig. 1B). The effects were specific because mRNA level for the G6PT, a transporter protein associated with the Glc-6-Pase complex, was not affected (Fig. 1C). Interestingly, mRNA for another gluconeogenic enzyme, i.e. the cytosolic form of phosphoenolpyruvate carboxykinase (PEPCK), was increased by the treatment with palmitate (Fig. 1D).


Figure 1
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  		Figure 1  Induction of Glc-6-Pase and PEPCK mRNA levels by palmitate and oleate in isolated rat hepatocytes. Freshly isolated rat hepatocytes (6 x 106 cells/100-mm dish) were incubated in RPMI 1640 medium containing glucose (5 mmol/L), without or with increasing concentrations of palmitate or oleate (0–100 µmol/L). After 4 h, total RNA was isolated and mRNAs for Glc-6-Pase (A,B), the cytosolic form of PEPCK (C), and G6PT (D) were measured by northern-blot analysis. For each panel, the blot shown is representative of 3 experiments. In each panel, the picture of ethidium bromide-stained gel depicting 18 S rRNA is shown to indicate sample loading.

 
That transcription is involved in the fatty acid effect shown in Fig. 1 is supported by 2 sets of data. In the first set, the transcriptional inhibitor actinomycin D blocked the fatty acid-induced increase in Glc-6-Pase mRNA (Fig. 2A); actinomycin D also blocked increase in Glc-6-Pase mRNA (Fig. 2B) induced by valerate and butyrate, 2 short-chain fatty acids that induce transcription from the Glc-6-Pase gene promoter (12). However, cycloheximide (a protein synthesis inhibitor) did not prevent fatty acid-induced stimulation of Glc-6-Pase mRNA accumulation (Fig. 2C), indicating that synthesis of new protein was not necessary for the fatty acid effect. The second set of data involved transcriptional read-out from the Glc-6-Pase gene promoter linked to the luciferase reporter gene transfected into H4IIE cells. In this cell line, as in primary cultures of rat hepatocytes, palmitate (100 µmol/L) as well as oleate (100 µmol/L) robustly increased Glc-6-Pase promoter activity (Fig. 3A,B). This effect is similar to that of short-chain fatty acids (12). At 10 µmol/L, the PUFA arachidonate had no effect on promoter activity (Fig. 3B). Together with the results of the actinomycin D experiments, these data demonstrate that saturated and monounsaturated fatty acids (typified by palmitate and oleate) up-regulate transcription of the Glc-6-Pase gene.


Figure 2
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  		Figure 2  Effect of actinomycin D or cycloheximide on fatty acid-induced increase in Glc-6-Pase mRNA level in rat hepatocytes. Hepatocytes (6 x 106 cells) were preincubated for 30 min without or with actinomycin D (0.01 mg/L) (A,B) or 0.01 mg cycloheximide/L (C) before the addition of fatty acids. For each experimental condition, total RNA was isolated after 4 h and Glc-6-Pase mRNA was measured by northern-blot analysis. Each blot was reprobed for 18 S rRNA to monitor sample loading. The concentration of palmitate or oleate was 100 µmol/L. Butyrate or valerate was added at 2.5 mmol/L.

 

Figure 3
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  		Figure 3  SFA (palmitate) and monounsaturated (oleate) fatty acids, but not PUFA (arachidonate) induce Glc-6-Pase gene expression in H4IIE cells. H4IIE cells were transfected with the –402/+66-LUC reporter gene construct. After 24 h, the cells were treated with palmitate (A) or oleate (B), each used at 100 µmol/L, or arachidonate (10 µmol/L). The cells were harvested 24 h later and processed for luciferase activity. The results are means ± SEM, n = 3 different cell cultures. (C) Induction of Glc-6-Pase mRNA level by palmitate in H4IIE cells. H4IIE cells (6 x 106 cells) were incubated in RPMI 1640 medium containing glucose at 5 mmol/L, in the absence or presence of increasing concentrations of palmitate, up to 100 µmol/L. (D) Effect of 2-bromopalmitate on Glc-6-Pase mRNA levels in isolated rat hepatocytes. Hepatocytes (6 x 106 cells) were incubated in serum-free medium containing glucose at 5 mmol/L and either palmitate (100 µmol/L) or 2-bromopalmitate (100 µmol/L). The relative abundance of Glc-6-Pase mRNA was determined by northern blotting after 4-h incubation. A representative northern blot is shown for C and D. Each blot was reprobed for 18 S rRNA to monitor sample loading. Values plotted are means ± SEM, n = 3–7 experiments. * Different from cells incubated in the absence of fatty acid, P < 0.05. (ANOVA followed by Fisher's multiple range test).

 
The H4IIE cell line possesses all the necessary components for the response to fatty acids as primary cultures of hepatocytes; this is apparent from the fact that palmitate increased the level of endogenous mRNA (for Glc-6-Pase) in H4IIE cells (Fig. 3C) as in freshly isolated hepatocytes (Fig. 1B). Oleate also had a similar effect (data not shown). To test whether the accumulation of Glc-6-Pase mRNA in response to saturated fatty acids required the metabolism of the fatty acid, hepatocytes were cultured for 4 h in the presence of 2-bromopalmitate (100 µmol/L), a nonmetabolizable analogue (14). This nonmetabolizable fatty acid had no effect on Glc-6-Pase mRNA level, indicating that metabolism of palmitate was essential for its stimulation of Glc-6-Pase gene expression (Fig. 3D). In other experiments (data not shown), we found that the t1/2 of the Glc-6-Pase mRNA was similar in the presence or absence of either palmitate or oleate, indicating that these fatty acids do not influence Glc-6-Pase mRNA degradation rate.

    Transcription factors recruited to the Glc-6-Pase gene promoter in response to palmitate. We previously reported that the transcription factor HNF-4{alpha} is recruited to the Glc-6-Pase gene promoter in response to short-chain fatty acids (12). In cells that were not treated with palmitate, HNF-4{alpha} robustly transactivated this gene promoter (Fig. 4A); in the presence of palmitate, this transactivation was doubled. PGC-1{alpha}, which has been shown to interact with the Glc-6-Pase gene promoter by binding to HNF-4{alpha} (15), also substantially increased promoter activity in the presence of palmitate (Fig. 4B).


Figure 4
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  		Figure 4  HNF4{alpha} and PGC-1{alpha} potentiate the transcriptional effect of palmitate on Glc-6-Pase gene promoter activity in H4IIE cells. H4IIE cells were transfected with –402/+66-LUC alone or with –402/+66-LUC and 100 ng of an HNF-4{alpha} expression plasmid (A) or 100 ng of a PGC-1{alpha} expression plasmid (B). After 24 h, the cells were untreated (control) or treated with palmitate (100 µmol/L) and harvested 24 h later for luciferase assay. The results are means ± SEM, n = 3 experiments. * Different from control, P < 0.05 (Mann-Whitney U test). ** Different from HNF-4{alpha} or PGC-1{alpha}, P < 0.05.

 
Because transcription factors never work alone at target gene promoters, we used ChIP assays to provide evidence of recruitment of HNF-4{alpha} as well as other transcription factors to the Glc-6-Pase gene promoter, in the context of the intact cell. Using 2 distinct primer sets, 2 segments of the promoter (–309/–184 and –209/+9) were studied as target regions, because Rajas et al. (11) showed that these 2 regions contain most of the regulatory elements necessary for nutrient response. Specifically, we monitored the recruitment of PPAR{alpha}, HNF-4{alpha}, HNF-3ß, CAAT/enhancer binding protein (C/EBP){alpha}, C/EBPß, sterol regulatory element binding protein-1, FOXO, cAMP regulatory element binding protein (CREB), NF-{kappa}B, and COUP-TF in isolated hepatocytes. In nonstimulated cells, all the transcription factors were bound at varying levels to the promoter (Fig. 5). The binding pattern was quite different in cells treated with palmitate. For example, in response to the fatty acid treatment, the binding of CREB to both regions was intense; the binding of HNF-4{alpha} was much more intense in region 2 (Fig. 5B) than in region 1 (Fig. 5A). In addition, there was increased binding of PPAR{alpha} but no dramatic changes in the binding of C/EBP{alpha}, chicken ovalbumin upstream promoter transcription factor (COUP-TF), NF-{kappa}B, and sterol regulatory element binding protein-1C. In the absence of any antibody (negative controls), no PCR signal was detected. These results indicate that in addition to HNF-4{alpha}, other transcription factors are recruited to the Glc-6-Pase gene promoter in vivo in response to palmitate.


Figure 5
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  		Figure 5  ChIP analysis of DNA from isolated rat hepatocytes incubated with or without palmitate. Hepatocytes were incubated without or with palmitate (100 µmol/L) for 1 h to assess association of various transcription factors with the Glc-6-Pase gene promoter. Results are representative of 2 independent experiments.

 

   Discussion
TOP
 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
LITERATURE CITED
 
Experiments performed several years ago demonstrated that fatty acids stimulate gluconeogenesis (16–20) by such mechanisms as supplying NADH and ATP needed for gluconeogenesis, providing acetyl-CoA that allosterically activates pyruvate carboxylase, and changing the redox state of the mitochondrial compartment (21). Diets rich in SFA increase, whereas diets rich in PUFA decrease the activity of the catalytic unit of Glc-6-Pase (9,10,22–24). Recently, we demonstrated that short- and medium-chain fatty acids cause an increase in the expression of this enzyme (12). Because palmitate and oleate are the major circulating fatty acids in plasma of mammals (25), we evaluated, in this study, the effects of these fatty acids on the expression of the Glc-6-Pase gene.

In this study, we show that oleate and palmitate induce the expression of the gene for Glc-6-Pase not only in adult rat hepatocytes but also in the H4IIE cell line. The mechanism of this induction is transcriptional and does not involve mRNA stability. These results are in sharp contrast to those reported for linoleate (26), which was shown to stabilize Glc-6-Pase mRNA in fetal rat hepatocytes. However, the physiological importance of the stabilization of Glc-6-Pase mRNA in fetal rat hepatocytes is problematic, because fetal liver does not carry out gluconeogenesis. Additionally, unlike hepatocytes from adult rats, Glc-6-Pase expression in hepatocytes from fetal liver is not altered in response to high glucose concentration (26). The fact that palmitate also increased PEPCK mRNA levels may suggest that, similar to the regulation of the expression of genes that code for lipogenic and glycolytic enzymes, SFA may coordinately regulate the expression of genes encoding gluconeogenic enzymes.

Our results revealed that the metabolism of palmitate was necessary for its induction of the Glc-6-Pase gene, because the nonmetabolizable analogue 2-bromopalmitate was ineffective. Our data also revealed that a variety of transcription factors (e.g. C/EBPß, CREB, and PPAR{alpha}) were recruited to the Glc-6-Pase gene promoter concurrently with HNF-4{alpha}, a transcription factor that is involved not only in hepatocyte differentiation and ureagenesis but also in the regulation of genes associated with glucose and fatty acid metabolism (27,28). The increased binding of HNF-4{alpha} and C/EPBß to the promoter in hepatocytes incubated with palmitate suggests that the C/EPB protein is also part of the fatty acid response of this promoter. Indeed, both C/EBPß and C/EBP{alpha} have been reported to be up-regulated in the ß-cell line MIN6 in response to palmitate and oleate (29). Recently, C/EBP proteins, in collaboration with HNF-4{alpha} and the coactivator CREB-binding protein, were shown to mediate the effects of cAMP on transcription from the Glc-6-Pase gene promoter (30).

Similar to HNF-4{alpha}, PGC-1{alpha}, the concentration of which is known to increase 2-fold following high-fat feeding (31), potentiates the positive transcriptional effect of palmitate. Increased expression of PGC-1{alpha} and HNF-4{alpha} occur during starvation and in diabetes (32), 2 physiologically important conditions in which Glc-6-Pase gene expression is also induced. At the present time, it is not obvious how the various transcription factors that have confirmed or putative binding sites on the Glc-6-Pase gene promoter (see schematic in Fig. 6A) interact to increase transcription from this promoter. However, because PGC-1{alpha} does not directly bind the Glc-6-Pase gene promoter (15), we hypothesize that interaction of PGC-1{alpha} with this promoter occurs through its binding to HNF-4{alpha}, which is recruited to the promoter in response to fatty acid (Fig. 6B). The HNF-4{alpha}-PGC-1{alpha} complex would then synergize with a C/EBPß-CREB complex to mediate full response of the promoter to the fatty acid treatment. In conclusion, our results reveal recruitment of an array of transcription factors to this promoter, which suggests that multiple regulatory elements in the promoter are responsible for the modulation of transcription of the Glc-6-Pase gene by long-chain fatty acids.


Figure 6
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  		Figure 6  Schematics of the Glc-6-Pase gene promoter. (A) Schematic of the –700/–66 region of the Glc-6-Pase gene promoter, indicating characterized and putative binding sites for known transcription factors and cofactors that regulate transcription of the gene. The schematic is based on published information on Glc-6-Pase gene transcription (15,30,33–39) and from recent unpublished work from our laboratory. (B) Model for transcriptional regulation of Glc-6-Pase gene promoter in response to palmitate. HNF-4{alpha} and C/EBPß constitutively bind the Glc-6-Pase promoter. In response to palmitate, there is increased recruitment of HNF-4{alpha}, which then recruits PGC-1{alpha}. The HNF-4{alpha}-PGC-1{alpha} complex would then synergize with C/EBP and CREB to mediate full response of the promoter to the fatty acid treatment.

 

   ACKNOWLEDGMENTS
 
We thank Dr. Richard W. Hanson for helpful discussion and for allowing the use of his laboratory during the performance of portions of this work. We also thank Dr. Yumiko Kawai for helpful discussion during the preparation of this manuscript and Dr. Chau-Kuang Chen for assistance with statistical analysis of the data.


   FOOTNOTES
 
1 Supported by grant no. 426839 (to D.M.) from the American Diabetes Association and the NIH grant DK-25541 to Richard W. Hanson and SO6-GM08037. Back

6 Abbreviations used: C/EBP, CAAT/enhancer binding protein; ChIP, chromatin immunoprecipitation assays; CRE, cAMP regulatory element; CREB, cAMP regulatory element binding protein; NF, nuclear factor; PEPCK, phosphoenolpyruvate carboxykinase; Glc-6-Pase, glucose-6-phosphatase; PGC-1{alpha}, PPAR{gamma} coactivator 1{alpha}. Back

Manuscript received 9 August 2006. Initial review completed 30 August 2006. Revision accepted 11 December 2006.


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 Materials and Methods
 Results
 Discussion
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