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Department of Biochemistry, Academic Medical Center, University of Amsterdam, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands
2 To whom correspondence should be addressed. E-mail: a.j.meijer{at}amc.uva.nl.
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ABSTRACT |
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 TOP ABSTRACT LITERATURE CITED |
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KEY WORDS: • cell volume • urea • aspartate shuttle • AMP kinase • mTOR
Although amino acids are substrates for the synthesis of a variety of N-containing compounds, it has become more and more clear over the years that these nutrients are also extremely important as regulators of fluxes through major metabolic pathways. In this short review this regulation is illustrated with a few examples, and some important recent developments are highlighted.
Examples of amino acids as regulators of metabolism
A textbook example of the control of metabolism by amino acids is the inhibition of L-type pyruvate kinase by alanine. This is considered to be of relevance in fasting because this regulatory mechanism, in addition to other mechanisms, helps to prevent the simultaneous occurrence of gluconeogenesis and glycolysis in hepatocytes.
Another famous example is the catalytic role of glutamate and aspartate in mediating the transfer of reducing equivalents across the mitochondrial membrane via the malate/aspartate shuttle (1), e.g., during aerobic glycolysis, in heart, skeletal muscle and brain, and during ethanol oxidation in the liver. Operation of the redox shuttle is unidirectional, against the direction of the redox potential difference across the mitochondrial membrane, because of the properties of the glutamate/aspartate translocator. This transport system mediates the efflux of negatively charged aspartate from the mitochondria in exchange for one molecule of glutamate and a proton, which is tapped from the mitochondrial proton gradient generated by the respiratory chain (2,3).
A third example of metabolic regulation by amino acids is at the heart of amino acid catabolism, i.e., in urea synthesis (4). Although the two N-donating molecules for the synthesis of one molecule of urea, ammonia and aspartate are derived from amino acid degradation with glutamate as intermediate, most textbooks ignore the fact that glutamate is also the substrate for the synthesis of N-acetylglutamate in the mitochondria, the essential activator of carbamoyl-phosphate synthase. Noteworthy is that in addition to its role as a component of the ornithine cycle, arginine accelerates synthesis of N-acetylglutamate because after its entry into the mitochondria, arginine stimulates N-acetylglutamate synthase activity. Thus, an increase in amino acid supply in the portal vein not only increases the rate of production of ammonia and aspartate for urea synthesis, but simultaneously increases the activity of existing carbamoyl-phosphate synthase molecules in the mitochondria. This results in a sigmoidal relationship between the ammonia concentration in the liver cell and the rate of urea synthesis, which allows large variations in urea synthesis at relatively constant ammonia concentrations (4). This is important because ammonia is not only toxic for the brain but is also an essential intermediary metabolite.
A fourth and beautiful example of metabolic regulation in which amino acids take part is the adaptation of N-metabolism to metabolic acidosis (4,5; for review). Under those conditions, urea synthesis is decreased to save bicarbonate for the neutralization of the excess of protons. In that case, multiple control mechanisms operate simultaneously. These include diminished amino acid transport across the hepatocyte plasma membrane, diminished synthesis of N-acetylglutamate, decreased activity of carbonic anhydrase V (which produces CO2 in the mitochondria for carbamoyl-phosphate synthase), decreased activity of hepatic glutaminase, increased activity of glutamine synthesis in pericentral hepatocytes and in muscle cells, increased renal glutaminase (to produce ammonia for excretion in the urine) and finally increased protein degradation in muscle (to produce more amino acids which, after oxidation of their negatively charged carboxylate groups, yield more bicarbonate).
Recent developments
Amino acids and changes in cell volume. A new avenue of metabolic regulation by amino acids in mammalian cells was opened more than a decade ago with the discovery that an increase in cell volume, associated with either amino acid transport or amino acid metabolism, has insulin-like effects on the fluxes through major metabolic pathways and that the effect could be mimicked by hypo-osmotically induced cell swelling (6–8). The notion that changes in osmolarity could affect metabolism was not new in itself, because it had been known for a long time that microorganisms can adapt to large changes in extracellular osmolarity by changing the activities of enzymes and/or transport systems, the purpose of which is to prevent a large difference in osmotic pressure across the cell membrane (9; for review). The new observation, however, was that the same principle is used by mammalian cells.
In our own research we were led by an old observation of Katz and colleagues (10) who showed that glycogen synthesis from glucose in hepatocytes depended on the presence of amino acids in the incubation medium. It took almost 15 years before the mechanism of this effect was unraveled. In collaboration with Baquet and Hue in Brussels (8; also communicated in reference 11), we showed that the ability of amino acids to stimulate glycogen synthesis in hepatocytes was related to their ability to increase the cell volume. This result was later confirmed in muscle cells (12). Simultaneously, and independently, Häussinger and colleagues studied the effect of cell swelling on glycogen degradation in the perfused liver and demonstrated that cell swelling inhibited and cell shrinkage stimulated glycogenolysis (6,11). These anabolic and anticatabolic effects of cell swelling were later extended to other metabolic pathways, such as protein degradation (13) and synthesis (14), fatty acid synthesis (15–17) and oxidation (18), as well as to processes dependent on membrane flow, such as autophagy (inhibited), exocytosis (stimulated), receptor-mediated endocytosis (stimulated) and bile flow (stimulated) (19,20; for review). These effects can be both short term or long term via changes in gene transcription (19,20). It must be stressed that the anabolic effects of amino acid–induced cell swelling are not confined to hepatocytes but are found in many different cell types (19,20).
Amino acid–induced cell swelling is due to concentrative, Na+-dependent transport of amino acids across the plasma membrane (driven by the transmembrane Na+ gradient, e.g., transport of glutamine, alanine, taurine) and to the intracellular production of impermeant catabolites, such as glutamate and aspartate (8, 19–22). In response to the initial cell swelling, cells undergo regulatory volume decrease and release KCl in an attempt to restore their original volume (19,20). The mechanism responsible for the stimulation by amino acids of glycogen synthesis from glucose may, at least in part, involve the decrease in chloride, which de-inhibits glycogen synthase phosphatase, and a rise in intracellular glutamate, which also activates glycogen synthase phosphatase (21). The same mechanism may be responsible for the stimulation of acetylCoA carboxylase by amino acids with similar effects of chloride and glutamate on the protein phosphatase, which mediates the dephosphorylation of acetylCoA carboxylase (16,17). There are also differences with regard to the regulation of the two systems by amino acids: for example leucine, which does not give rise to cell swelling because its transport is not Na+-coupled (8), activates acetylCoA carboxylase activity in hepatocytes but has no effect on glycogen synthase activity (23) or on glycogen synthesis (8). However, in muscle cells leucine does stimulate glycogen synthesis (24).
Intracellular glutamate may also be responsible for the inhibition of fatty acid oxidation by amino acid–induced cell swelling because it directly inhibits carnitine palmitoyltransferase (18). It has been proposed that mitochondrially produced glutamate may act as an intracellular messenger that couples glucose metabolism to insulin secretion by ß-cells, because, after its efflux from the mitochondria, glutamate accumulates in the insulin-containing granules, causes them to swell and stimulates exocytosis (25,26). Although this is a very attractive mechanism, it must be stressed that high cytosolic glutamate concentrations do not always seem to correlate with high rates of insulin production (27).
Apart from these specific mechanisms involving changes in chloride and glutamate concentrations, amino acid–induced cell swelling may also influence metabolism by changes in macromolecular crowding. Because of their high intracellular concentration, proteins may often be in close proximity to each other, and cell volume-induced changes may affect their interaction and thus the kinetic properties of enzymes (20). In this context it is also possible that the cytoskeleton is involved in sensing cell volume changes and that this affects enzymes associated with it (19,20). Examples of cytoskeleton-bound enzymes are glycogen synthase (28) and acetylCoA carboxylase (29). It would be of great interest to find out whether amino acid–induced changes in cell volume do, indeed, influence enzyme compartmentation in the cytosol (30).
An illustration of the effect of cell swelling on glycogen production can be found in hepatic encephalopathy when astrocytes synthesize and accumulate large amounts of glutamine because of the rise in blood ammonia (31). Under these conditions, astrocytes are filled with glycogen (32). Because glycogen contains large amounts of crystal water, this may further add to astrocyte swelling and thus to the increase in intracranial pressure that is observed under these conditions.
Amino acids, autophagy and signal transduction. Because the relationship between amino acids, signal transduction and protein synthesis will be dealt with elsewhere in this issue, I will only briefly highlight the major findings and put them in a historical context.
Next to the regulation of glycogen synthesis, a regulatory mechanism that has also greatly interested us over the years is the inhibition of autophagy by amino acids and, in connection with this, inhibition of proteolysis. Autophagy is a very active process in the liver, but it occurs in all cell types. The first step of this complicated process, in which cytoplasmic material is sequestered in autophagosomes before the fusion of these vesicles with lysosomes, is inhibited by amino acids (33; for review). The stimulation of glycogen synthesis and the inhibition of autophagy by amino acids strongly resemble the effects of insulin; however, the specificity of the amino acid regulation of the two pathways is clearly different, although they also share a common element. Among the various amino acids, leucine (together with phenylalanine and tyrosine) is most potent in inhibiting autophagy (33) but, as indicated above, this amino acid does not affect glycogen synthesis. Although amino acid–induced cell swelling can inhibit autophagy on its own (13), swelling also potentiates the inhibitory effect of low concentrations of leucine (34). In this context it is of interest to note that early experiments with perifused hepatocytes under steady-state conditions had indicated that low concentrations of leucine and alanine synergistically inhibited autophagic proteolysis (35). Furthermore, omission of K+ from the perfusion medium prevented the inhibition by the two amino acids (35). It is tempting to conclude from these experiments that the link between amino acid–mediated cell swelling and repression of autophagy is K+. However, it is also possible that a rise in intracellular chloride was responsible for acceleration of proteolysis under these conditions. This may be because in the absence of extracellular K+ the Na+/K+ pump will be inhibited, causing the plasma membrane potential to collapse.
Indications that changes in cell volume may be an important factor in the control of protein metabolism in vivo was provided by Häussinger et al. (36) and Finn et al. (37). In these studies, a clear relationship was found between muscle cell volume and the whole-body nitrogen balance in a large number of critically ill patients, and the loss of muscle cell water in these patients exceeded the loss of protein (37). Stimulation of proteolysis by cell shrinkage has also been implicated in cold preservation–induced liver injury and methods aimed at preventing the decrease in cell volume have been shown to inhibit proteolysis and to improve graft function (38,39).
Like the stimulation of glycogen synthesis by amino acids, the mechanism responsible for inhibition of autophagic proteolysis by amino acids remained obscure for decades. Although we are still far from understanding the details, a key to the mechanism was provided by our discovery that addition of a physiological mixture of amino acids to hepatocytes resulted in a strong and rapid phosphorylation of ribosomal protein S6 (40,41). This protein is a component of the 40S ribosomal subunit and is one of the endpoints of insulin signaling; the phosphorylation of S6 is required for the translation of a class of mRNA molecules encoding proteins of the protein-translation machinery (42). To our surprise, however, insulin alone did not affect S6 phosphorylation but potentiated the effect of low, but not of high, amino acid concentrations. Among the various amino acids, leucine in combination with phenylalanine and tyrosine were most effective, and hypo-osmotically induced cell swelling, like insulin, promoted the effect of low amino acid concentrations. In the presence of cycloheximide to prevent simultaneous protein synthesis, there was an approximately linear relationship between the degree of phosphorylation of S6 and the percentage inhibition of autophagic proteolysis under a wide variety of conditions. Amino acid–stimulated phosphorylation of S6 was completely prevented by rapamycin, indicating that the serine/threonine protein kinase mTOR3 was upstream of S6 in the amino acid signaling pathway (40,41). Moreover, rapamycin addition could partially, albeit not completely, overcome the inhibition of autophagic proteolysis by amino acids. An explanation for the partial effect of rapamycin may be that leucine is also an inhibitor of the lysosomal proton pump (43). We concluded that the same signaling mechanism is involved in the opposite control of protein synthesis (stimulation by amino acid–dependent signaling) and protein degradation (inhibition by amino acid–dependent signaling), which would be efficient from the point of view of metabolic regulation (41). Interestingly, rapamycin also stimulated autophagy in yeast cells under nutrient-rich conditions (44), indicating conservation of this control mechanism in evolution.
After these initial observations, the occurrence of amino acid–dependent signaling (with leucine as the most active amino acid) was described for many cell types and the synergy was confirmed between insulin and amino acids with regard to their effect on the phosphorylation state of mTOR downstream targets, including p70S6 kinase (70 kDa S6 kinase), 4E-BP (eukaryotic protein-translation initiation factor 4E-binding protein-1) and other proteins (45,46; for review).
There is general consensus that amino acids do not affect protein kinase B, in contrast to the action of insulin. There is still discussion about whether or not PI 3-kinase (phosphatidylinositol 3-kinase) is affected by amino acids. The confusion is that the amino acid–induced phosphorylation of mTOR downstream targets is prevented by inhibitors of PI 3-kinase (33,45), but that successful attempts to show activation of PI 3-kinase in the presence of amino acids were scarce and many attempts failed (45). As discussed in detail elsewhere (47), PI 3-kinase might be on a pathway parallel to that of amino acids, and the activation of both PI 3-kinase (by insulin) and mTOR is required for full activation of at least some of the mTOR downstream targets, such as p70S6 kinase (48,49).
Whether or not amino acids are able to increase PI 3-kinase activity, the anomalous inhibition of autophagy by PI 3-kinase inhibitors led us to the hypothesis that PI 3-kinase class III may be essential for autophagy (33,50). This lipid kinase produces PI(3)P constitutively, in contrast to PI 3-kinase class I, which is stimulated by insulin to produce PI(3,4,5)P3. There is now strong evidence that PI(3)P is, indeed, an essential component of the autophagic system (51–53). In this context it is of interest to note that 3-methyladenine, the classical inhibitor of autophagy, proved to be an inhibitor of PI 3-kinase (50).
How amino acids affect mTOR-mediated signaling is as yet unclear. Although the presence of a plasma membrane amino acid receptor was postulated (54) recent evidence indicates that amino acid transport across the plasma membrane is required before the amino acids can activate mTOR (55). An attractive mechanism involves the inhibition of a protein phosphatase by amino acids, which would explain the synergy between amino acids and insulin (45,46; for review). However, experiments with protein phosphatase inhibitors were not always conclusive (47; for review). According to very recent data of Krause et al. (56) there are two protein phosphatases in the amino acid signaling pathway. One protein phosphatase is located upstream of mTOR and may be identical to the glutamate-activated protein phosphatase that is also responsible for activation of acetylCoA carboxylase (17) (see above). A second protein phosphatase is located downstream of mTOR, inactivates p70S6 kinase and becomes inhibited when mTOR is activated (Fig. 1). The existence of two protein phosphatases would explain the discrepancies in results in the literature obtained with protein phosphatase inhibitors, because the outcome of such experiments would have depended on the experimental protocol used, i.e., whether the protein phosphatase inhibitor had been added before or after exposure of cells to amino acids (56).
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Apart from the fact that amino acid–dependent signal transduction is rapamycin-sensitive, there is also direct evidence that amino acids can increase mTOR phosphorylation and/or mTOR activity in intact cells (60,61). The recently discovered protein raptor, a regulatory protein that is associated with mTOR (hence its name) and is required for mTOR kinase activity, may be part of the amino acid–sensing mechanism (62,63).
An interesting new development is the discovery that mTOR not only senses the intracellular concentration of amino acids but also that of ATP (59). Presumably, AMP kinase is part of the sensing mechanism because activation of this protein kinase strongly inhibits amino acid–dependent signaling (56,64–66) and protein synthesis (64,65).
Downregulation of insulin signaling by amino acid–dependent signaling. Despite the fact that amino acids and insulin synergize in activating mTOR downstream targets, there is increasing evidence that in muscle cells, adipocytes and hepatoma cells, amino acids cause a rapamycin-sensitive down-regulation of insulin-induced activation of PI 3-kinase, protein kinase B and of glucose transport (67–71). This is caused by increased ser/thr phosphorylation of IRS-1 (insulin receptor substrate-1), decreased binding of the p85 regulatory subunit of PI 3-kinase to IRS-1, followed by (presumably proteasomal) degradation of IRS-1 (68,69). Because amino acid–induced down-regulation of IRS-1 will cause inhibition of glucose transport (see above), this mechanism may underlie diminished glucose consumption during high-protein feeding (67,68).
It thus appears that amino acids and insulin synergize with regard to the activation of mTOR and its downstream targets and thereby influence protein metabolism; yet, amino acids appear to inhibit the initial part of the insulin signaling pathway. This part is known to control glucose transport and metabolism (67,72). Paradoxically, as discussed earlier, amino acids do stimulate glucose conversion into glycogen. Although this is confusing, the paradox may be resolved by the differences in amino acid specificity. Leucine is particularly effective in activating mTOR-dependent signaling and in down-regulating glucose metabolism, whereas amino acids that increase cell volume (e.g., glutamine, alanine) stimulate glycogen synthesis. Interestingly, feeding fish protein protects against glucose intolerance and insulin resistance induced by a high-fat diet, and concentrations of leucine, tyrosine and some other amino acids in the plasma were significantly lower in rats fed cod protein as compared to those fed casein (68; and references therein).
Amino acid signaling and insulin production in ß-cells. A fascinating observation is that amino acid signaling also occurs in ß-cells and that it promotes insulin production by stimulating ß-cell proliferation (73–75). This further adds to the anabolic properties of amino acids. Also in these cells, leucine is effective in stimulating the phosphorylation of mTOR downstream targets. It is perhaps not by accident that in ß-cells the combination of glutamine and leucine is very effective in stimulating both signaling (74) (as it is in hepatocytes (23)) and insulin production (27). As noted earlier, cell swelling synergizes with leucine with regard to mTOR-dependent signaling and glutamine is potent in causing cell swelling. In the past, the effect of leucine on insulin production was ascribed to its ability to activate glutamate dehydrogenase and thus to provide citric acid cycle intermediates and to increase mitochondrial ATP production (27,74). Interestingly, inhibition of mitochondrial ATP production interfered with the signaling pathway (74). Although overall ATP levels did not change (74), it is possible that AMP was increased under these conditions and that activation of AMP kinase may have been responsible for this observation. It would not be surprising if part of the stimulation of insulin production by glucose was caused by a decrease in the activity of AMP kinase (76), resulting in activation of amino acid–dependent signaling in ß-cells. In this view, proper functioning of the malate-aspartate shuttle in ß-cells (77) may also help to keep the activity of AMP kinase low. Although hypothetical still, these are intriguing possibilities that deserve to be explored.
Concluding remarks
From the foregoing discussion it is clear that amino acids, in addition to their role as intermediary metabolites, are important anabolic signals. Mechanisms are based on the ability of some amino acids to cause cell swelling (e.g., glutamine and alanine) and on the ability of other amino acids (leucine in particular) to mimic some, but not all, of the effects of insulin on signaling (see Fig. 1 for summary). The ability to stimulate signaling and insulin production in pancreatic ß-cells further adds to the anabolic properties of amino acids.
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FOOTNOTES |
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3 Abbreviations used: 4E-BP, eukaryotic protein-translation initiation factor 4E-binding protein-1; mTOR, mammalian target of rapamycin; PI 3-kinase, phosphatidylinositol 3-kinase; PI(3)P, phosphatidylinositol 3-phosphate; PI(4,5)P2, phosphatidylinositol 4,5-bisphosphate; PI(3,4,5)P3, phosphatidylinositol 3,4,5-trisphosphate; p70S6k, 70 kDa S6 kinase.
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