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Regulation of Mammalian Gene Expression by Glucose

Guy A. Rutter, Jeremy M. Tavaré and D. Gail Palmer

G. A. Rutter, J. M. Tavaré, and D. G. Palmer are in the Department of Biochemistry, School of Medical Sciences, University of Bristol, Bristol BS8 1TD, UK.

	Abstract

 
Recent data suggest that cells from species as diverse as yeast and mammals may use similar mechanisms to detect changes in nutrient concentration. Here we review recent advances in understanding how glucose regulates gene transcription in mammals.

	Introduction

Top Introduction Classes of nutrient-regulated... Regulation of L-PK and... The FAS and ACC... How are the transcription... Kinase cascades and the... Regulation of the insulin... Conclusions and perspectives References

 
Recognizing nutrients is a fundamental problem for all living cells. For simple organisms, such as bacteria and yeast, it's a question of life and death. For example, when their preferred carbon source, glucose, is unavailable, bacteria activate genes that enable them to use lactose through the familiar lac operon. Similarly, germinating plant seeds must switch from stored fuel sources to utilizing carbohydrates synthesized as soon as the seedling is capable of photosynthesis. In complex animals, including mammals, the job of sensing changes in nutrient concentration in the blood and responding with the expression of genes involved in storing the sugar is performed by highly specialized cell types. These fall into two groups. The first major cell/tissue group comprises those that must accumulate and store glucose when the concentration in the blood rises—namely liver, skeletal muscle, and adipose tissue. The second group is made up of specialized neuroendocrine cells that provide hormonal cues to other cells. The most important of these "command and control" cells are located in the pancreas in specialized microorgans called islets of Langerhans. Islet ß-cells secrete insulin when blood glucose rises, whereas islet -cells release the stress hormone glucagon when it falls. Understanding how islet cells sense changes in the concentration of blood glucose is an important question for human health since defective glucose-stimulated insulin release is a contributory factor in non-insulin-dependent diabetes mellitus (NIDDM). Possibly providing an even higher level of control are glucose-sensitive neurons in the ventromedial hypothalamus, which may then modulate ß-cell function through neuronal means as well as affect feeding behavior.

Until recently, research into the intracellular signaling mechanisms whereby glucose regulates genes in mammalian cells has been undertaken largely without reference to simpler organisms. However, it is becoming apparent that similar mechanisms may be involved in both cases and may have been conserved through evolution for a billion or more years. In principle, glucose could act on target cells either by binding to the receptor at the cell surface or through its metabolism. In bacteria and mammals, both systems are involved, though in mammals only one mechanism is used by any given cell. Although taste bud cells on the tongue sense glucose through a cell surface receptor, glucose sensing by islet, liver, adipose, and muscle cells almost certainly involves metabolism of the sugar. Here we will survey those genes in animals that are transcriptionally regulated by glucose through its intracellular metabolism.

	Classes of nutrient-regulated genes

Top Introduction Classes of nutrient-regulated... Regulation of L-PK and... The FAS and ACC... How are the transcription... Kinase cascades and the... Regulation of the insulin... Conclusions and perspectives References

 
Glucose increases the expression of genes whose protein products catalyze important regulatory steps in the pathways of lipid synthesis (Table 1) (3, 15). In the liver, the glucokinase gene is transcriptionally activated by insulin through a "direct" intracellular signaling mechanism that is independent of extracellular glucose. Similarly, induction by insulin of sterol regulatory element binding protein/adipocyte determination differentiation dependent factor 1 (SREBP/ADD1; see below), an important transcription factor in the regulation of the fatty acid synthase (FAS) gene, is independent of external glucose. We will refer to these as "purely insulin-responsive" (pIR) genes. In contrast, several genes appear to be responsive to both insulin and to glucose (GIR genes). For example, the phospho-enol pyruvate carboxykinase (PEPCK) and glucose 6-phosphatase genes are repressed by insulin both through glucose-dependent and -independent mechanisms.

View larger version (21K): [in this window] [in a new window]   FIGURE 1. Likely signaling pathways involved in the regulation of glucose-sensitive genes. In the ß-cell, glucose enters cell via GLUT2 transporter and is metabolized by glucokinase (GK) to glucose 6-phosphate (G6P)/xylulose 5-phosphate (X5P), leading to activation of glucose/insulin responsive (GIR) genes. In liver, activation of insulin receptor initiates expression of purely insulin-responsive (pIR) genes such as GK, which is required for metabolism of glucose. In adipose tissues, insulin stimulates translocation of GLUT4 transporter to plasma membrane, which promotes uptake of glucose into cell. In adipocytes, glucose is metabolized to G6P/X5P by hexokinase (HK).

	Regulation of L-PK and S14 genes

Top Introduction Classes of nutrient-regulated... Regulation of L-PK and... The FAS and ACC... How are the transcription... Kinase cascades and the... Regulation of the insulin... Conclusions and perspectives References

 
The critical regulatory regions of both of these genes are similar and located approximately –1440 bp upstream of the transcriptional start point in the S14 gene and at –160 bp in the L-PK gene. DNA fingerprinting reveals no change in the occupancy of the L-PK promoter during stimulation of liver cells by glucose (A. Kahn, personal communication). Each of these promoter elements includes a tandem repeat of a so-called E (enhancer) box. These 6-bp palindromic sequences with the structure 5'-C(C/A)NG(T/G)G are based on the Herpes simplex virus major-late transcription factor binding site (CACGTG). In the L-PK and S14 promoters, the two E boxes (together called the glucose or carbohydrate response element) are separated by 5 bp. Although the sequence of this region is unimportant, deviations from 5-bp spacing dramatically decrease the responsiveness to glucose, presumably indicating that transcription factors bound at each E box must interact and be located on the same face of the DNA. Adjacent to this E box region of both promoters is a binding site for an ancillary factor, which in the case of the L-PK gene is likely to be hepatic nuclear factor-4 (HNF4).

The ubiquitous and abundant transcription factor upstream stimulatory factor (USF) binds efficiently to oligonucleotides derived from the L-PK and S14 E boxes. USF is encoded by two genes (USF1 and USF2) and is a member of the basic/helix-loop-helix/leucine zipper (b/HLH/LZ) family. To investigate the in vivo role of USF in binding and transactivation via the L-PK and S14 E box regions, the groups of A. Kahn in Paris and H. C. Towle in Minneapolis have used similar approaches, yet with apparently conflicting conclusions. Thus A. Kahn's group found that expression of truncated USF constructs, capable of heterodimerization but lacking a DNA binding domain, blocked L-PK induction by glucose in hepatocytes. Similarly, targeted gene disruption by homologous recombination has implied crucial roles for the USF gene products USF1 and USF2a/b (a and b being splice variants). However, long periods of incubation (3 days) are required for the effects of dominant-negative USF on hepatoma cells, whereas nonconditional knockouts always bear the risk of developmental alterations indirectly related to the disrupted gene. Indeed, H. C. Towle's group observed that dominant-negative versions of USF had no effect on glucose induction of L-PK in primary cultured hepatocytes, when much shorter post-transfection periods were used. However, Kennedy et al (6) used direct microinjection and imaging techniques (12) to demonstrate that anti-USF1 or -USF2 antibodies strongly and specifically inhibited L-PK promoter activation by elevated glucose, providing strong evidence for USF2 involvement in islet ß-cells.

Emerging data now suggests that another factor, chick ovalbumin upstream promoter-transcription factor II (COUP-TFII), may be involved in regulating the L-PK gene. Using a yeast "one-hybrid" screen to identify proteins capable of binding the L-PK E box, A. Kahn's group have demonstrated that COUP-TFII, a zinc-finger binding protein, is a likely binding protein at this site (Kahn et al., personal communication). Although USF was also identified in this screen, another factor recently implicated in the regulation of glucose-sensitive gene expression, SREBP (see below), was not. Overexpression of COUP-TFII reversed the trans-activation of the L-PK promoter by USF2 and, in the model proposed by Kahn, may bind to the most 5' E box in the L-PK promoter region.

	The FAS and ACC genes

Top Introduction Classes of nutrient-regulated... Regulation of L-PK and... The FAS and ACC... How are the transcription... Kinase cascades and the... Regulation of the insulin... Conclusions and perspectives References

 
The FAS gene carries only one E box element, centered approximately –60 bp upstream of the transcriptional start point. This site appears to confer responsiveness to insulin and glucose (10), whereas the role of a second, canonical E box in the first intron (centered at +290 bp) is unclear. As well as binding USF, consensus E boxes are able to bind the transcription factor called SREBP or ADD. There are two SREBP genes in mammals, SREBP-1 and SREBP-2. SREBP-1 gives rise to two alternatively spliced forms. SREBP-1c is expressed in liver and adipose tissue, and SREBP-1a is expressed in hepatoma cell lines. Transgenic animals overexpressing SREBP-1 suffer from a dramatic increase in hepatic triacylglycerol deposition. SREBP binds a consensus response element, 5'-ATCACCCCAC, present in genes responsible for sterol biosynthesis, as well as to consensus E boxes (CACGTG). Indeed, it is conceivable that SREBP could interact with the distal E box of the S14 gene. However, it is uncertain whether SREBP is capable of binding to the L-PK E box (CACGGG) or proximal S14 E box (CACAGG), which differ at least at one position from the consensus E box sequence (CACGTG).

SREBP activity is regulated in a complex manner. Low cholesterol levels provoke the release from the endoplasmic reticulum of the active NH₂-terminal fragment of SREBP via proteolytic cleavage of a precursor form. The released fragment, which contains the b/HLH/LZ domain responsible for DNA binding, then migrates to the nucleus, leading to transcriptional activation of target genes. Using a TyrAla mutant that fails to bind DNA but is able to dimerize with endogenous SREBP, P. Ferré's group report a powerful inhibition of FAS, ACC, S14, and L-PK gene expression in hepatoma cells. H. C. Towle's group replicate these data with a truncated SREBP entirely lacking the DNA binding domain—but with a twist: wild-type, unmutated SREBP acts identically to the truncated protein. This may imply that overexpression is titrating an SREBP binding protein, which may be acting as a receptor for the glucose-derived signal.

In summary, there is good evidence for the occupancy of the FAS E box by SREBP but less for a role of this factor in interacting with the S14 and L-PK genes. Mice in which SREBP-1 has been ablated by targeted disruption may provide clues, although this model is limited by the fact that ablation of SREBP-1 results in a compensatory increase of SREBP-2 and no clear phenotype. It is thus possible that a number of transcription factors may bind to the different carbohydrate response elements but that another ancillary protein represents the true "receptor" of the glucose-generated signal.

The ACC gene is expressed from distinct promoters in a tissue-specific manner. Promoter II is controlled by glucose, believed to act not via an E box but instead through a GC-rich hexanucleotide site that binds another ubiquitously-expressed transcription factor, Sp1.

	How are the transcription factors regulated—is there a soluble "mediator"?

Top Introduction Classes of nutrient-regulated... Regulation of L-PK and... The FAS and ACC... How are the transcription... Kinase cascades and the... Regulation of the insulin... Conclusions and perspectives References

 
The simplest mechanism would initially involve a small, diffusible molecule derived from glucose metabolism. Subsequently, regulation of glucose-sensitive genes may then involve changes in the phosphorylation state of key proteins. G6P or the pentose phosphate pathway intermediate xylulose 5-phosphate (X5P) may be the key triggering intermediate (3, 15). Xylitol, the precursor of X5P, activates L-PK gene in hepatoma cells and suppresses PEPCK expression in vivo. X5P activates protein phosphatase 2A, potentially providing a link with a requirement for a protein dephosphorylation event.

Evidence for a role of G6P stems from the observation that 2-deoxyglucose (DOG), which is metabolized to DOG6P but no further, induces FAS expression in adipocytes. By contrast, 3-orthomethyl-glucose, which enters liver and fat cells but is not metabolized, is ineffective. P. Ferré's group have reported a close correlation between G6P concentration and FAS mRNA in cultured hepatocytes and adipocytes but none with X5P. Unambiguous answers to these questions may well require microinjection of nonmetabolizable forms of these putative coupling molecules (e.g., DOG6P), and single cell analysis of gene expression (6, 12).

However, analogy with plants and yeast suggests an alternative mechanism. In plants, hexokinase (HK) acts not just to catalyze metabolic flux but also, by a mechanism that is not yet defined, to generate a signal. In genetic studies, plant HK complements the metabolic function of the yeast HK but not the ability of HK substrates to regulate gene expression. Thus HK itself, perhaps through an increase in the level of a phosphorylated intermediate, may initiate a signaling cascade. This model is analogous to the role of the phospho-enol pyruvate-carbohydrate phosphotransferase system in bacteria. Here glucose controls the levels of the phosphorylated form of one component of this system, called IIA^Glc, by accepting the phosphoryl group from this protein. Since phospho-IIA^Glc maintains adenylate cyclase activity, decreased levels of phospho-IIA^Glc in response to glucose diminish intracellular cAMP concentrations and inhibit cAMP-activated genes. A perplexing feature of any equivalent mammalian system is that glucokinase activity predominates in the liver and in islet ß-cells, whereas low-K_m HK isoforms are operative in adipose tissue.

	Kinase cascades and the role of AMP kinase

Top Introduction Classes of nutrient-regulated... Regulation of L-PK and... The FAS and ACC... How are the transcription... Kinase cascades and the... Regulation of the insulin... Conclusions and perspectives References

 
Inhibition of protein phosphatases 1 and 2A with okadaic acid completely blocks the ability of glucose to induce the FAS gene in liver cells (2, 8). The search is therefore on for the protein kinases and/or phosphatases involved. One possible candidate is AMP-activated protein kinase (AMPK), a metabolic stress-activated enzyme and serine/threonine-specific kinase, which is stimulated by AMP. AMPK is also activated through phosphorylation by an upstream kinase (AMPKK), which is itself activated by AMP. Since intracellular AMP concentrations increase steeply as ATP levels fall, AMP provides a sensitive detector of metabolic status. Incubation of liver cells with the AMPK activator 5-aminoimidazole-4-carboxamide-1-ß-D-ribofuranose (AICAR) prompts the inactivation of L-PK, S14, and FAS genes, suggesting that a decrease in AMPK activity could be involved in the effects of glucose.

Active AMPK is a heterotrimer of -, ß-, and -subunits, with catalytic activity possibly residing in the -subunit (4). Molecular cloning of the AMPK subunits has revealed striking similarity to the products of the Saccharomyces cerevisiae Snf (for sucrose nonfermenting) gene family—AMPK subunits 1 and 2 of Rattus norvegicus correspond to Snf1p of S. cerevisiae; the ß-subunits (ß1 and ß2) are similar to Sip1p, 2p, and Gal83p; subunits 1, 2, and 3 show similarities to Snf4p. The activity of the yeast Snf1 kinase is increased by at least an order of magnitude during the switch from glucose-containing to sucrose-containing medium. During this transition, there is a transient but dramatic increase in intracellular AMP concentration, which recovers after the induction of genes that allow growth on sucrose (in particular the invertase gene). Snf1 phosphorylates the Tip1p subunit of the nuclear repressor of invertase (and other genes), termed mig1 (for mannose-insensitive gene). Phosphorylation of this subunit causes its export from the nucleus, prompting transcription of glucose-repressed genes.

Although regulation of AMPK under metabolic stress is well documented in animal cells, changes in AMPK activity in response to hormones and glucose have been less easy to detect. Early studies in which the activity of the AMPK substrate 3-hydroxy-3-methylglutaryl-CoA reductase was followed in the liver demonstrated diurnal changes, implying AMPK activity fluctuations. However, direct enzymatic assay failed to reveal differences in liver AMPK activity, which also failed to materialize after stimulation of liver cells with insulin or glucose (D. G. Hardie, personal communication). However, Salt et al. (13) have recently reported that, in ß-cell-derived INS-1 and HIT-T15 cells, AMPK activation and AMP levels are both suppressed since the glucose concentration rises over the range that activates insulin secretion. These assays were performed by immunoprecipitation and using a specific peptide based around a Ser-Ala-Met-Ser (SAMS) motif of ACC. Given the difficulty of assaying AMPK activity, it seems possible that closer inspection may reveal that AMPK is indeed under the control of glucose and insulin.

	Regulation of the insulin gene by glucose

Top Introduction Classes of nutrient-regulated... Regulation of L-PK and... The FAS and ACC... How are the transcription... Kinase cascades and the... Regulation of the insulin... Conclusions and perspectives References

 
The insulin gene, expressed only in islet ß-cells, is regulated transcriptionally by glucose (1). Important cis-acting elements, located within 350 bp of the transcriptional start site, have been defined by deletion analysis. Particularly important are four sites, A1, 2, 3, and 5, that bind the homeodomain transcription factor pancreatic/duodenum/Xenopus 1 (PDX-1, also called IPF-1, IUF-1, STF-1, or IDX-1), whereas sites binding the factors RIPE3B, USF, and E47 may also be important. Systematic mutagenesis suggests that the A3 site is important for induction by glucose. Increased occupancy of the A3 site is observed with elevated glucose. Both A1 and A3 sites include a TAATG/C motif, the canonical recognition sites for homeodomain proteins. This observation led to the eventual cloning of PDX-1, a factor expressed strongly only in islet ß-cells, some gut cells, and (much more weakly) in pancreatic exocrine cells (J. Egan, personal communication). Human mutations in this factor cause a hereditary form of maturity-onset diabetes of the young (MODY4), and transgenic mice heterozygous for PDX-1 expression (pdx-1 +/–) develop diabetes. Homozygous disruption or mutation of the gene causes pancreatic agenesis both in mice and humans. At the molecular level, overexpressed myc-epitope-tagged PDX-1 migrates from the cytosol to the nucleus of glucose-stimulated ß-cells (11). This may be associated with an apparent change in molecular mass from 31 to 46 kDa (the calculated relative mass of the full-length 283-amino acid protein is 34 kDa). However, convincing immunocytochemical evidence for the activated translocation of the endogenous protein, at normal levels of expression, is presently unavailable. Intriguingly, chimaeras between PDX-1 and GFP are located exclusively within the nucleus and are unresponsive to glucose (11). This suggests that addition of the bulky (27-kDa) fluorescent protein at either end of PDX-1 may disrupt an interaction with a binding protein involved in the cytosol-to-nucleus translocation.

How may glucose transmit a signal to activate PDX-1? Data from K. Docherty's group suggest that the stress-activated members of the mitogen activated protein (MAP) family of protein kinases may be critical. One of these is termed variously p38, reactivating kinase (RK) or stress-activated protein kinase-2 (SAPK2) and is implicated from the use of the inhibitor SB-203580, which blocks the effect of glucose on PDX-1 DNA binding. Although direct data reporting the activation of SAPK have been lacking, a kinase believed to lie immediately downstream, MAPKAPK2, is activated, consistent with SAPK stimulation. Data from K. Docherty's group, and that of G. A. Rutter, also indicate that glucose may exert these effects via phosphatidylinositol 3-kinase (PI3K). With the use of in-gel kinase assays, we have now also found in rat islets a protein kinase with apparent molecular mass of 63 kDa that is capable of phosphorylating the SAPK substrate ATF-2 (a transcription factor) is activated by elevated glucose concentrations (16 vs. 3 mM). Intriguingly, all of the above data suggest that elevated glucose concentrations may act to increase one type of cellular stress (osmoticSAPKs) and decrease another (metabolicAMPK).

Could insulin gene activation by glucose be mediated by released insulin? Since insulin secretion requires increases in intracellular Ca²⁺ concentration, whereas activated insulin gene expression may not, this argues against a role for the released hormone. However, others have suggested that increases in intracellular Ca²⁺ concentration are important for insulin gene expression. As suggested by recent data from I. Leibiger et al. in Stockholm (9), Docherty in Aberdeen, and ourselves (G. A. Rutter and H. J. Kennedy, unpublished data), exogenous insulin may activate insulin gene expression directly. Even more dramatically, ß-cell-specific ablation of the insulin receptor (7) produces mice that are glucose intolerant and show a drastically reduced first phase of glucose-induced insulin release—a phenotype strikingly similar to NIDDM. These observations also provide an explanation for the impact on ß-cell function of mutations in the insulin receptor substrate IRS-2. These ideas are summarized in Fig. 2.

View larger version (10K): [in this window] [in a new window]   FIGURE 2. Potential signaling pathways involved in transcriptional regulation of insulin gene () in ß-cell. WM, wortmannin. In ß-cell, glucose is metabolized to G6P (which may act as a signaling metabolite), prompting an increase in intracellular ATP concentration, which then inhibits an ATP-sensitive K+ channel in plasma membrane. Subsequent lowering of membrane potential promotes uptake of Ca2+ into cell via a voltage-sensitive Ca2+ channel, and this in turn stimulates secretion of insulin from intracellular stores. Binding of insulin to its receptor in plasma membrane may then initiate a signaling cascade ultimately activating expression of insulin gene.

	Conclusions and perspectives

Top Introduction Classes of nutrient-regulated... Regulation of L-PK and... The FAS and ACC... How are the transcription... Kinase cascades and the... Regulation of the insulin... Conclusions and perspectives References

	Acknowledgments

 
We thank Dr. I. Leclerc for critical reading of the manuscript.

Work in our laboratories is supported by the Medical Research Council (UK), the Wellcome Trust, The British Diabetic Association (BDA), The Biotechnology and Biological Sciences Research Council, The European Community, and the Royal Society of London.

J. M. Tavaré is a BDA Senior Research Fellow.

	References

Top Introduction Classes of nutrient-regulated... Regulation of L-PK and... The FAS and ACC... How are the transcription... Kinase cascades and the... Regulation of the insulin... Conclusions and perspectives References

 

1. Docherty, K., and A. R. Clark. Nutrient regulation of insulin gene expression. FASEB J. 8: 20–27, 1994.[Abstract]
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