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Department of Biochemistry and Molecular Pharmacology, School of Medicine, West Virginia University, Morgantown, WV
3To whom correspondence should be addressed. E-mail: Lsalati{at}hsc.wvu.edu.
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ABSTRACT |
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 TOP ABSTRACT LITERATURE CITED |
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KEY WORDS: • RNA splicing • posttranscriptional • gene expression • polyunsaturated fat
Changes in the nutritional status of an animal have profound affects on metabolism. During starvation, tissues that store energy mobilize these reserves; liver and adipose tissues are key sites of energy storage. Fatty acids are released from adipose tissue and glucose is released from liver glycogen stores to provide energy substrates for the body. During refeeding, glycogen stores are replenished and excess dietary energy is converted to triacylglycerol for storage. The nutrient composition of the diet is a key regulator of flux through the metabolic pathways by which energy homeostasis is achieved. Dietary monosaccharides such as glucose and fructose stimulate the activity of enzymes involved in converting glucose to fatty acids. PUFA inhibit the activity of these lipogenic enzymes.
De novo fatty acid biosynthesis utilizes the activities of ATP-citrate lyase, acetyl-CoA carboxylase, fatty acid synthase, malic enzyme, and glucose-6-phosphate dehydrogenase (G6PD) to convert carbon substrates and reducing equivalents into palmitate. The activities of these enzymes are coordinately regulated so that flux of substrate to fatty acids is high when energy is in excess and low when fatty acids are being used as a source of energy. A change in the activities of the lipogenic enzymes involves regulation at a number of steps. Regulation of the catalytic efficiency of an enzyme is only observed with acetyl-CoA carboxylase and is caused by phosphorylation inhibiting enzyme activity and by allosteric stimulation by citrate or inhibition by long chain fatty acyl CoAs. Longer-term changes in enzyme activity are caused by changes in the amount of the enzyme protein in the cell. Nutritional status affects the amounts of fatty acid synthase, acetyl-CoA carboxylase, ATP-citrate lyase, and malic enzyme by causing large changes in the rate of transcription of these genes, enhancing mRNA levels and ultimately enzyme protein synthesis [reviewed in (1)]. In contrast, starvation, refeeding, or diet composition do not regulate transcription of the G6PD gene, despite large changes in the amount of G6PD mRNA (2). Production of G6PD mRNA requires the efficient and correct processing of the primary transcript. G6PD enzyme activity is regulated by changes in the rate of mRNA processing. It is this latter topic that is the focus of this review.
Cellular roles of G6PD
G6PD is an essential activity in all cells. As the first and rate-determining step of the pentose phosphate pathway, its most important function is the production of NADPH for protection against oxidative agents in all cells and in the liver and adipose tissue for the synthesis of fatty acids. Deficiency of G6PD causes hemolytic anemia in response to consumption of fava beans, viral illnesses, and drugs such as antimalarial agents, sulfonamide antibiotics, nonsteroidal anti-inflammatory agents, and even aspirin. This is one of the more prevalent deficiency diseases throughout the world. It is caused by point mutations within the coding region of the gene resulting in a relative decrease in G6PD enzyme activity, and never by frame shift mutations, large deletions, alternative splicing, or nonsense mutations (3). These latter mutations must be lethal, as is a "knock-out" of G6PD activity (4–7). G6PD deficient individuals are also hypolipidemic, displaying both decreased serum cholesterol and triacylglycerol concentration (8,9), underscoring the relevance of G6PD activity for reductive biosynthetic reactions. Whereas G6PD enzyme activity is expressed in all cells, only liver and adipose tissue are specially adapted to regulate G6PD synthesis in response to diet and hormones. Changes in the expression of G6PD in these tissues correlate with the rate of fatty acid biosynthesis (10).
Mechanisms regulating expression of G6PD
Translational/posttranslational mechanisms. Regulation of G6PD enzyme activity by nutritional status involves intracellular signals generated by both hormones, such as insulin, and metabolites of dietary nutrients, such as monosaccharides and PUFA. The generally accepted dogma is that G6PD activity does not undergo allosteric or covalent modifications in response to nutritional modifications. However, phosphorylation of G6PD has been observed and it causes a coincident decrease in G6PD activity in endothelial cells incubated in high glucose concentrations (11). This phosphorylation is mediated via cAMP and protein kinase A. Although changes in G6PD amount by any of these mechanisms have not been observed during dietary manipulations, a change in the catalytic efficiency of G6PD has the potential to provide temporal regulation of cellular G6PD activity.
The effects of nutrients on G6PD activity are caused by comparable changes in the amount of enzyme protein, the relative rate of enzyme protein synthesis, and the rate of degradation of G6PD (Fig. 1). Changes in G6PD enzyme activity due to starvation and refeeding or dietary fat are accompanied by similar changes in the amount of the G6PD protein (12–15). When examined over a variety of nutritional and hormonal conditions in both liver and adipose tissue, changes in G6PD activity are also accompanied by similar changes in the rate of enzyme synthesis (12–14,16–21). For example, a 13-fold or more increase was observed in both the relative rate of synthesis for G6PD protein and G6PD enzyme activity in the livers of rats switched from a chow to a high-sucrose diet (16). Similarly, during dietary fat consumption, the rate of G6PD protein synthesis decreased 96% coincident with a 91% decrease in G6PD enzyme activity (15). Changes in the rate of degradation due to hormonal or nutritional modifications are less clear. A decrease in the half-life of the G6PD enzyme from 16 h to 6 h was observed in rat liver due to consumption of a high-fat diet (22), whereas others did not observe an effect of fat on the rate of enzyme disappearance (12). Because changes in enzyme synthesis can account for the change in enzyme activity, regulation is thought to be pretranslational; however, any changes in enzyme protein turnover would serve to enhance the rapidity by which the cell can alter the amount of G6PD activity.
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Changes in amount of mature mRNA can involve transcriptional regulation of the gene or a posttranscriptional mechanism, such as mRNA stability, the processing of the pre-mRNA (including splicing and polyadenylation of the pre-mRNA), and nucleocytoplasmic transport. As measured using nuclear run-on assays, the rate of G6PD transcription was constant during starvation, refeeding a high-carbohydrate diet, or the inclusion of polyunsaturated fat in the diet (24). Similar results were observed for G6PD regulation by insulin, glucose, and arachidonic acid in rat hepatocytes in primary culture (30). Furthermore, the transcriptional activity of the G6PD gene occurs at a very low rate, as low as the transcriptional rate of the fatty acid synthase or stearoyl-CoA desaturase genes measured during starvation. While the transcriptional activity of fatty acid synthase and stearoyl-CoA desaturase increase 30-fold or more during refeeding, G6PD gene transcription remains unchanged despite 27- to 30-fold increases in G6PD mRNA (24). These results indicate that nutritional regulation of G6PD gene expression is posttranscriptional.
Numerous steps are required between transcription of an mRNA and its translation in the cytoplasm and regulation has been described at many of these steps. Dietary iron can affect both the stability of the transferrin receptor mRNA and the translation of the ferritin mRNA (32). Glucose has been observed to enhance the stability of the Glut-4 mRNA (33) and the fatty acid synthase mRNA (34). These effects involve changes in the amount of mRNA in the cytoplasm. The steps by which primary transcripts are processed to mature mRNA are located in the nucleus. To determine the location of regulation of G6PD mRNA amount, total RNA was isolated from both nucleus and the cytoplasm of mouse livers during both the starvation/refeeding and the low-fat/high-fat dietary protocols. With both protocols, all of the change in amount of G6PD mRNA in the cytoplasm could be accounted for by a similar change in the amount of G6PD mRNA in the nucleus (23). Thus, not only is the regulation of G6PD expression occurring at a post-transcriptional step, this step is in the nucleus.
Regulation of G6PD mRNA splicing. The nucleus can be fractionated into the nuclear membrane, the soluble nucleoplasm, and the insoluble nuclear fraction, which contains newly transcribed mRNA (35–37). Determining the amount of G6PD pre-mRNA in this fraction provided an experimental tool to measure pre-mRNA that was both newly synthesized and undergoing processing, and to separate it from mature mRNA at the nuclear pore (the nuclear membrane fraction). The fractionation protocol was validated using Western analysis with antibodies against SRm160 and NuMA, specific proteins in the insoluble fraction. Total RNA was isolated from each fraction and the amount of G6PD mRNA was measured using an RNase protection assay and probes that hybridized across exon intron boundaries. These probes detected a long fragment (exon 2-intron 2; intron 8-exon 9) corresponding to unspliced RNA that contains both the exon and intron sequences and a smaller fragment (exon 2; exon 9) corresponding to spliced mRNA that contains only the exon sequences (23,38). The terms unspliced and spliced must be used cautiously because each probe provides information about the splicing of only 1 of the 12 introns in the G6PD gene.
G6PD unspliced RNA was found predominantly in the nuclear insoluble fraction whereas mature G6PD mRNA was present in all fractions (38). Furthermore, the amount of G6PD spliced RNA in the insoluble fraction increased in mice that were starved and then refed and decreased in mice consuming the high-fat diet. Thus, regulation of G6PD mRNA occurs during mRNA processing. To determine the step during mRNA processing that is regulated by nutritional status, we measured the rate of accumulation of G6PD RNA that was unspliced, partially-spliced, spliced, uncleaved, and polyadenylated in mice that were starved and then refed the high-carbohydrate diet. RNase protection assays and the strategy described above were used to quantify the amounts of RNA. Figure 2 provides a diagrammatic format for these results. The rate of transcription (k1) of the G6PD gene is not regulated (24,30). Thus, changes in the amount of G6PD mRNA must result from changes subsequent to this step. A decrease in rate at any step would result in an increase in the rate at which that mRNA specie is degraded. In this regard, mRNA that is not completely polyadenylated or spliced is degraded and this degradation appears to occur in the nucleus (39–41). The results of 2 types of experiments were consistent with regulation during splicing (k2). Using a probe that hybridized to exon 8-intron 8-exon 9-intron 9 and RNase protection assays, we detected 3 types of G6PD RNA: the full length unspliced RNA, partially spliced RNA representing splicing of intron 8, and 2 fragments corresponding to exons 8 and 9 and representing fully spliced mRNA (38). Refeeding stimulated an accumulation of partially spliced mRNA (ratio of partially spliced/unspliced RNA-3 vs. 1 for the refed vs. starved mice, respectively). Continued splicing further stimulated mRNA accumulation (ratio of fully spliced/unspliced RNA-20 vs. 5, refed vs. starved, respectively). Thus, the regulated increase in G6PD mRNA accumulation involves events during splicing and not merely stabilization of the mature mRNA.
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The same approach was used to determine the intranuclear step regulated by dietary polyunsaturated fat. Hepatic G6PD mRNA undergoes a daily variation due to food intake. At the start of the dark (feeding) cycle, the level of G6PD mRNA is very low. As the mice consume the low-fat diet, the amount of mature G6PD mRNA increases 7-fold or more (23); this increase occurs after a lag of 2 to 4 h. Consumption of a diet high in polyunsaturated fat results in a 50% decrease in the amount of hepatic G6PD mRNA at the beginning of the dark cycle and the attenuates the feeding induced increase (23). The increase in G6PD mRNA in the livers of mice fed a high-fat diet reflects the stimulation in gene expression due to the carbohydrate in the diet. To measure only gene expression effects due to dietary fat, RNA was isolated and G6PD mRNA quantified during the first 4 h of the feeding cycle. Feeding mice a high-fat diet resulted in a 60 to 70% decrease in the amount of spliced G6PD mRNA in the nuclear insoluble fraction of mouse liver (38). In contrast, at these same time points the amount of unspliced G6PD RNA in the nucleus did not increase (Fig. 3). This is consistent with our results demonstrating that transcription of the G6PD gene is not regulated by polyunsaturated fat (24) and is the first independent verification of this. Thus, dietary fat inhibits the accumulation of mature G6PD mRNA. Furthermore, dietary fat also inhibits the accumulation of partially spliced RNA (Fig. 3). The rate of accumulation of partially spliced to unspliced RNA was decreased in mice fed the high-fat diet, suggesting that the splicing reaction itself is inhibited by dietary PUFA.
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Regulation of mRNA processing
Posttranscriptional regulation in the nucleus.
Regulated splicing often involves the activity of splicing coactivator proteins in the nucleus. These regulatory proteins are typically members of the SR family of splicing coactivators and their activity is regulated by phosphorylation and dephosphorylation (44–47). The phosphorylation of SR proteins by specific kinases in the nucleus results in a change in their intranuclear location (48,49). Phosphorylated SR proteins are observed at the site of transcription and dephosphorylation results in an accumulation of SR proteins in interchromatin granules (50). Activation of an SR protein upon phosphorylation may be a consequence of this change in location within the nucleus, a change in the proteins interacting with the phosphorylated form of the protein, or a change in RNA binding activity (46,47,51). Binding of these proteins to the pre-mRNA and subsequent recruitment of the spliceosome mediate the activity of SR proteins in enhancing splicing. The sequence in the pre-mRNA is termed the exon splicing enhancer. Most studies of regulated splicing have focused on the role of SR proteins and exons splicing enhancers in alternative exon inclusion; however, G6PD mRNA is not alternatively spliced. Only a few reports have examined how humoral factors regulate splicing efficiency, and G6PD is one of them. Other examples include regulated expression of thymidylate synthase during the cell cycle, which requires both the thymidylate synthase promoter and a spliceable intron, which need not be from the thymidylate synthase mRNA (52). Splicing of the tumor necrosis factor-
mRNA requires a cis-acting element in the 3'-UTR of the transcript (53). Thus, diverse mechanisms appear to be involved in nuclear posttranscriptional regulation. With this in mind, we sought to determine if an exon splicing enhancer element was involved in the regulation of G6PD mRNA splicing by nutritional status.
Defining the response element involved in G6PD regulation. To define the response element in G6PD pre-mRNA, we designed a pre-mRNA reporter assay. The G6PD gene is 18 kb long and contains 13 exons. Thus, RNA reporter plasmids were constructed containing subsets of the 18 kb gene (54). Expression of the mRNA reporter was driven by the CMV promoter, which is not regulated by arachidonic acid. The reporter plasmids were transiently expressed in primary rat hepatocytes. The reporter plasmids express mouse mRNA. RNase protection assays and a riboprobe to a variant region of exon 13 can distinguish between transcripts produced from the RNA reporter plasmid and those produced from the endogenous rat gene. The amount of reporter mRNA was measured in hepatocytes treated with and without arachidonic acid to determine if the produced mRNA contained a sequence that conferred regulation by polyunsaturated fatty acid. An RNA reporter plasmid (pCMV7–13, 3'-UTR) containing DNA between intron 6 and the 3' end of the gene was robustly expressed in rat hepatocytes incubated with insulin. Incubation of the rat hepatocytes with arachidonic acid resulted in a 51% decrease in the level of reporter transcripts [Fig. 4 (54)]. The decrease in the reporter transcript expression was similar to the decrease in the amount of rat G6PD mRNA, indicating that the regulation of reporter transcript expression mirrored the regulation of the endogenous G6PD gene. Furthermore, inhibition of reporter mRNA amount by arachidonic acid was observed when the G6PD 3'-UTR was replaced with the SV40 UTR, consistent with the lack of involvement of polyadenylation in regulation by nutritional factors (Fig. 4).
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To further define the element, successive 5'-deletions were made in the reporter construct so that the reporter mRNA produced was shorter and shorter. The inhibition by arachidonic acid was maintained until exon 12 was deleted [Fig. 4 (54)]. This loss of regulation was not due to the absence of splicing signals in this construct because the abundance of mRNA produced from RNA reporters containing G6PD introns and exons 5' of intron 6 were not regulated by arachidonic acid. To further verify that the mRNA sequences 3' of intron 11 had regulatory activity, the region of DNA including 63 nt of exon 12 and the 3'-end of the gene was ligated to ß-galactosidase and expressed in hepatocytes. The mRNA produced from this reporter was decreased by incubation with arachidonic acid. In contrast, expression of the exon 12 sequences in the context of the G6PD cDNA in the absence of introns was not inhibited by arachidonic acid, whereas restoring intron 12 to this plasmid restored inhibition by arachidonic acid (54). Thus, exon 12 contains a cis-acting element involved in regulating splicing of G6PD mRNA.
Regulation of G6PD expression in the primary hepatocytes by arachidonic acid recapitulates the regulation observed in the intact animal with dietary polyunsaturated fat both in the magnitude of the inhibition, the time course in which the inhibition takes place, and regulation during splicing. Additional evidence from our laboratory suggests that exon 12 is also involved in regulation in the intact animal (54). Using the same mRNA mapping strategy and probes to pre-mRNA to exon 12 and surrounding introns, we observed an increase in pre-mRNA containing exon 12 and intron 11 in mice fed a high-fat diet. This increase was observed despite a 50% inhibition in the amount of mature mRNA in these mice. Thus, splicing is inhibited, resulting in a decrease in the production of the mature mRNA. These results are consistent with the presence of a splicing regulatory element in or near exon 12 that is involved in regulation by both dietary fat in the intact mouse and arachidonic acid in primary rat hepatocytes.
When a mRNA is not spliced efficiently or polyadenylated, the cell must degrade the aberrant RNA. Two pathways have been described for degradation of RNA in the nucleus. In the first pathway, mRNA that is not completely processed does not leave the site of transcription in the nucleus (39–41). Specific proteins recruited to the mRNA by the spliceosome complex most likely "mark" correct splicing and initiate export of the mRNA to the cytoplasm (55–57). In the absence of proteins to initiate export, the mRNA can become a target for degradation. In yeast and in mammalian cells, degradation appears to be catalyzed by a complex of exonucleolytic enzymes called the nuclear exosome (41,58). Many questions remain, such as how in a multi-intron transcript is the correct and complete splicing of all introns detected resulting in release of the transcript? What proteins or signals recruit the exosome to a mRNA?
A second pathway of nuclear RNA turnover is used in the degradation of mRNA containing premature termination codons. Certain mRNAs containing premature termination codons are degraded within the nucleus at the site of their transcription (59). This nuclear nonsense mediated decay pathway appears to need either a Kozak consensus sequence or an internal ribosomal entry site in the mRNA. Scanning in the nucleus by some component(s) of the translational machinery detects the premature termination codon and targets the mRNA for degradation (60). While G6PD mRNA does not contain a premature termination codon, an inefficiently spliced pre-mRNA retains one or more introns, which give the appearance of an mRNA containing a premature stop codon. It remains to be determined if the nuclear exosome is also recruited to degrade incompletely spliced messages, such as G6PD.
Future directions
A model for regulation of G6PD by dietary status is presented in Figure 5. A pool of nascent transcripts is produced from the G6PD gene at a constant rate. In mice fed a high-carbohydrate, low-fat diet the transcript is cotranscriptionally spliced and polyadenylated. The fully processed mRNA is released from the transcription site and exported to the cytoplasm. We hypothesize that the efficient processing of G6PD mRNA is facilitated by the binding of a splicing coactivator (SR protein) to an exon splicing enhancer in exon 12. The activity of the splicing coactivator is most likely regulated by phosphorylation (active)/dephosphorylation (inactive). When mice consume a diet high in fat, binding of the coactivator is inhibited, possibly by a decrease in its phosphorylation. In the absence of this coactivator, splicing occurs less efficiently and the transcript retains intron(s). The incompletely processed mRNA is not released from the site of transcription and is degraded in the nucleus. Future experiments are aimed at testing this model. These experiments will provide new data on posttranscriptional regulation per se and define a new pathway by which nutrients regulate gene expression.
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FOOTNOTES |
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2 This work was supported by grant DK46897 from the National Institutes of Health.
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LITERATURE CITED |
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