Current Opinion in Clinical Nutrition & Metabolic Care:
PROTEIN, AMINO ACID METABOLISM AND THERAPY: Edited by Olav Rooyackers and John Brosnan
The role of amino acid transporters in nutrition
Poncet, Nadège; Taylor, Peter M.
Division of Cell Signalling & Immunology, College of Life Sciences, University of Dundee, Sir James Black Centre, Dundee, UK
Correspondence to Peter M. Taylor, Division of Cell Signalling & Immunology, College of Life Sciences, University of Dundee, Sir James Black Centre, Dundee DD1 5EH, UK. Tel: +44 1382 384961; fax: +44 1382 385507; e-mail: email@example.com, http://www.lifesci.dundee.ac.uk/people/peter_taylor/
Purpose of review: We consider recent advances in epithelial amino acid transport physiology and our understanding of the functioning of amino acid transporters as sensors, as well as carriers, of tissue nutrient supplies.
Recent findings: Gut hormones (e.g. leptin) may regulate intestinal amino acid transporter activity by a variety of mechanisms, although the overall functional significance of such regulation is not yet fully understood. Important functional interactions between amino acid transporters and nutrient-signalling pathways which regulate metabolism [e.g. the mammalian target of rapamycin (mTOR)C1 pathway which promotes cell growth] have been revealed in recent studies. Amino acid transporters on endosomal (e.g. lysosomal) membranes may be of unexpected significance as intracellular nutrient sensors. It is also now evident that certain amino acid transporters may have dual receptor–transporter functions and act as ‘transceptors’ to sense amino acid availability upstream of signal pathways.
Summary: Increased knowledge on the timescale of the amino acid sensor-signal-effector process(es) should help in the optimization of protein-feeding regimes to gain maximum anabolic effect. New opportunities for nutritional therapy include targeting of amino acid transceptors to promote protein-anabolic signals and mechanisms up-regulating amino acid transporter expression to improve absorptive capacity for nutrients.
The recommended daily allowance (RDA) for dietary protein intake by an adult person is 0.8 g/kg/day, irrespective of overall energy intake , although protein requirements increase during periods of growth, rehabilitation and pregnancy. The amino acid constituents of this protein must move across cell membranes in order to be absorbed, assimilated and metabolized by bodily tissues. Amino acids do not readily diffuse across lipid membranes and require membrane-spanning transporter protein ‘pores’ to help them translocate across cell membrane barriers. This process requires a number of steps: amino acid binding to a specific exposed site on a transporter; a resultant conformational change in the protein which exposes the amino acid to the opposite membrane face through its central pore; amino acid release and reorientation of the transporter to the initial conformation. The amino acid binding sites of mammalian amino acid transporters generally accept a range of structurally similar amino acids, such that transport of a given amino acid across a particular cell membrane may be mediated by multiple transporters with overlapping substrate specificities (see Table 1). Furthermore, transport of a specific amino acid across a membrane or epithelial layer may depend on the integrated activity of several parallel functioning amino acid uniporters and antiporters, sometimes coupled to movements of ions including Na+, H+, K+ and/or Cl− (see Table 1; Fig. 1). A classical ‘System’-based classification of amino acid transport mechanisms in mammalian cells has more recently metamorphosed into classification based on similarity between transporter gene sequences ([2–4]; see also Table 1). Whilst the bulk of amino acids transported across cell membranes are L-amino acid (L-AA), certain amino acid transporters also have specific roles in transport of biologically relevant amino acid derivatives [e.g. LAT1 for thyroid hormones, L-3,4-dihydroxyphenylalanine (L-DOPA) ] and the PAT and ASCT transporter families in particular are also characterized by a relatively low stereoselectivity for L-AA (e.g. [7▪]) giving them particular importance for transport of small, biologically active D-amino acid (D-AA; e.g. D-Ser).
Dietary protein of high quality includes sufficient amounts of the dietary essential (or indispensable) amino acids (EAAs): Leu, Ile, Val, Phe, Trp, Met, Thr and Lys. The EAAs include both neutral amino acids and cationic amino acids, and several have important metabolic/biosynthetic functions beyond their role as components for protein synthesis. For example, tryptophan is a precursor for serotonin and nicotinamide synthesis, whilst methionine is a methyl-group donor for nucleotide synthesis. Dietary amino acids in excess of those required for protein synthesis or particular metabolic purposes are rapidly catabolized, typically as oxidative fuels. Anionic amino acids are not dietary-essential nutrients, but, alongside other nonessential amino acids (NEAAs), are important metabolic intermediates and hence represent a significant potential source of dietary energy.
AMINO ACID TRANSPORTERS AND ABSORPTION
Dietary protein is hydrolysed by digestive proteases to absorbable constituents which include dipeptides and tripeptides as well as amino acids. Active amino acid and peptide absorption is driven by Na+ and H+ electrochemical gradients established by the Na+/K+ ATPase pump at the epithelial basolateral membrane. The major absorptive amino acids and peptide transport systems are shown in Fig. 1b. The relative importance of peptide and free amino acid absorption at the luminal membrane is not clearly established and may depend on the protein composition of the meal (e.g. how easily hydrolysed are the constituent peptides) [8,9]. Peptides are absorbed by H+-coupled symport and are largely hydrolysed to amino acids in the epithelial cells, although some peptides are absorbed intact into the bloodstream [8,9]. Neutral and anionic amino acids are taken up into intestinal epithelial cells by Na+-coupled symport (‘co-transport’), whereas cationic/dibasic amino acids are transported largely by an amino acid antiport (‘exchange’) mechanism (see Fig. 1). Most EAAs are neutral and are absorbed apically through B0AT1 and ASCT2, the cationic EAA lysine being absorbed apically through b0,+AT. All amino acids pass from the epithelial cell to the bloodstream by amino acid antiport and/or facilitative efflux systems. In particular, glutamine/EAA antiport at the basolateral membrane provides the dual benefit of providing glutamine as an intestinal fuel whilst completing the absorption of EAA into the bloodstream.
Inherited disorders of epithelial amino acid transport such as cystinuria (rBAT/ b0,+AT defect), Hartnup disorder (B0AT1 defect) and lysinuric protein intolerance (LPI; y+LAT1 defect) have provided important information on the physiological properties of amino acid transporters (e.g. [5▪▪] for review). The effects of a functional amino acid transport defect due to mutations in an individual transporter rarely result in a specific amino acid deficiency syndrome linked to failure of intestinal absorption, because of the overlapping substrate specificities of amino acid transporters. Nevertheless, the aminoaciduria typical of the renal phenotype of these disorders will increase dietary requirement for any affected EAA. The most ‘at-risk’ EAAs (for affected individuals on lower-marginal protein diets) appear to be tryptophan and lysine (absorption affected by Hartnup disorder and cystinuria/LPI, respectively). These EAAs can be delivered in peptide form to Hartnup  and cystinuria  patients, but not readily to those with LPI [12▪]. In contrast to other transport disorders, LPI actually results in protein intolerance due to an impaired ability to detoxify protein N through the urea cycle (Arg/Orn are important urea-cycle intermediates provided to hepatocytes by y+LAT1) [12▪]. LPI also reveals a plausible link between y+LAT1 activity and nitric oxide signalling, which is overactive in LPI because intracellular levels of the nitric oxide precursor Arg are raised and which may lead to immune dysfunctions [12▪].
The absorptive capacity for nutrients (including amino acids and peptides) by the intestine is typically maintained at a higher level than the normal dietary supply (allowing a so-called biological ‘safety factor’ to ensure effective absorption of a high-protein meal) . Absorptive capacity can be regulated with respect to chronic alterations in quantity and quality of dietary protein. Intestinal amino acid transporter expression is known to be induced by raised levels of dietary protein or free amino acid mixtures (maximizing energy intake) and may also increase at protein intakes below those required for EAA balance to ensure supply of these essential nutrients . During the fasted state, the intestinal epithelium receives a nutrient supply from the bloodstream, notably a supply of glutamine as an oxidative fuel. At least in mice, the contribution of PepT1 to overall intestinal amino acid absorption appears to be more important when high-protein loads reach the intestine, under which circumstances the rate of protein hydrolysis in the lumen or at the brush border membrane and/or the amino acid absorptive capacity may become increasingly limiting, leading to a higher availability of intact dipeptides and tripeptides for absorption through PepT1 .Nevertheless, peptide transport does not appear to be nutritionally essential, as PepT1-null mice are viable and without any obvious abnormalities despite dramatic reductions in intestinal peptide transport capacity . The cellular mechanisms underlying regulation of amino acid and peptide transporter expression and activity in the intestine remain poorly understood, although it is clear that several endocrine factors may be involved. Epidermal growth factor (EGF) augments intestinal adaptation and both B0AT1  and ASCT2  are activated downstream of EGF signals. In ischaemic injured intestinal cells, down-regulation of ASCT2 protein expression and mRNA transcription is reversed by EGF action . EGF and growth hormone also prevent the loss of ASCT2 gene expression in resected small intestine . Leptin, a key satiety signalling molecule, positively regulates PepT1 expression and transport capacity in the intestine when secreted into the gut lumen . Given that gastric leptin secretion should increase with a high dietary protein load, this mechanism might be seen to contribute to maintenance of the absorptive ‘safety factor’ for amino acid nutrition. In contrast to this view, B0AT1 and ASCT2 protein abundance in the apical membrane of intestinal cells is down-regulated by leptin [22,23▪]. To add further complexity, there is also recent evidence for rapid regulation of intestinal amino acid transport activity in intact intestine involving local neural circuits . Furthermore, surface expression of several amino acid transporters in the small intestine (e.g. B0AT1, b0,+AT) involves interaction with accessory proteins (here ACE2, rBAT, respectively [3,25]) which may also regulate their functional activity. A new study [26▪] demonstrates that B0AT1 may also form a functional protein complex with the intestinal peptidase aminopeptidase N (APN), forming a ‘metabolon’ which channels luminal amino acids from digested dietary protein to the amino acid transporter for absorption.
AMINO ACID TRANSPORTERS IN CELLULAR NUTRITION AND SIGNALLING
The amino acid transporters at the plasma membrane of cells forming mesodermal tissues are broadly distinct from those in epithelial cells, although from the same gene families. In general, EAAs are taken up by exchange or facilitative mechanisms, whereas NEAAs tend to be transported by concentrative Na+-coupled transport (see Fig. 1a). This results in certain NEAAs (especially glutamine and alanine) becoming highly concentrated in certain cell types, notably in skeletal muscle, where they have been suggested to function at least partly as labile nitrogen stores [27,28]. EAAs tend to have similar concentrations in intracellular and extracellular fluids. Amino acid transporter activity and substrate competition are important factors in the determination and regulation of amino acid fluxes between mammalian tissues (‘inter-organ amino acid nutrition’), dependent on the physiological and nutritional state of the whole body (see, e.g.  for review). In the fed state the predominant amino acid flux is from the intestine to other tissues, whereas in the postabsorptive state the dominant amino acid fluxes are between muscle, liver and kidney. In the latter state, EAA/glutamine antiporters in tissues such as skeletal muscle (see Fig. 1a) simultaneously provide EAAs for muscle protein synthesis whilst boosting glutamine availability in the blood for other tissues to use either as a fuel (e.g. lymphocytes, intestinal epithelium) or as an aid to maintaining optimum acid-base and nitrogen stasis (e.g. liver, kidney) [28–30].
Nutrient ‘sensors’ are now well established as integral components of nutrient-regulated signalling pathways controlling cell growth, proliferation and metabolic rate [31–33]. The major amino acid sensing-signalling pathways in mammalian cells are the general control nonrepressible (GCN) and mammalian target of rapamycin (mTOR) pathways, both of which utilize amino acid transporters in sensor and effector arms of their respective pathway functions (e.g. [34–36]; see [32,33,37] for review). Mammalian cells sense amino acid availability at least partly by sampling the intracellular amino acid pool(s) associated with biomolecules effecting protein turnover. In the case of the GCN pathway, which is activated when amino acids are scarce, this involves detection of the level of amino acid ‘charging’ on tRNA bound to the GCN2 protein kinase . The amino acid-sensing mechanism(s) of the mTOR pathway, which is activated when amino acids are abundant, is more complex, but recent research has revealed components including leucyl-tRNA synthetase [38▪] and the vacuolar H+-ATPase (vATPase) [39▪▪], which are required for amino acid-dependent recruitment of the mTOR protein kinase (within the multiprotein mTORC1 complex) to lysosomal membrane compartments (Fig. 2). This latter discovery, which appears to be associated with amino acid accumulation into lysosomes [39▪▪], has raised interest in the possibility that amino acid transporters on endosomal membranes play a role in amino acid sensing and adds merit to more detailed study of the molecular biology of lysosomal amino acid transporters such as the PATs (see e.g.  for a ‘classical’ functional review and  for the latest findings). PAT1, PAT2 and PAT4 may all have either endosomal or plasma membrane localization, although their amino acid substrate selectivity differs from the range of amino acids activating mTORC1 [7▪,43], and they seem most likely to exert a negative influence on lysosomal mTORC1 signalling by mediating H+-dependent efflux of amino acids (produced by proteolysis) from the endosomal lumen into the cytosol [39▪▪]. Nevertheless, certain EAAs (e.g. tryptophan and derivatives) act as inhibitors of PAT2 transport function [7▪], and, although it is not known whether this contributes to a signalling role, PATs remain interesting new targets for modulation of mTORC1 signalling . Another putative link between PATs and mTORC1 signalling arises from the observation that activation of mTORC1 by nutrients is associated with migration of lysosomes from the perinuclear region to the peripheral cytosol, a process apparently driven by changes in intracellular pH  which might conceivably be linked to altered rates of H+-amino acid symport through PATs coupled to activity of the endosomal (vacuolar) H+-ATPase complex [39▪▪] (see Fig. 2). There is also growing evidence that mammalian amino acid transporters such as PAT1, PAT4 and SNAT2 may act as amino acid receptors (i.e. amino acid substrate binding to the transporter protein induces an intracellular nutrient signal independent of amino acid transport) and thus act as multifunctional ‘amino acid transceptors’ [33,45▪], an arrangement whereby PAT1 and SNAT2 monitor intra-cellular and extra-cellular amino acid concentrations, respectively, can be readily envisaged. SNAT transporters have also been implicated in mediating the central response to EAA deficiency within the anterior piriform cortex (APC) of the brain, although they do not appear to be the primary EAA sensors [46▪▪]. This response allows animals to rapidly make food selections on the basis of EAA quality (i.e. to choose food containing an adequate complement of EAA).
The anabolic drive generated by a protein meal derives from a combination of nutritional and endocrine (largely growth factor) signals, and the mTORC1 pathway has a central, positive role in co-ordinating these signals to optimize cellular protein turnover and, when appropriate, tissue growth [31,32]. The increase in EAA availability after protein or amino acid ingestion is now known to up-regulate expression of amino acid transporters (e.g. SNAT2, LAT1) in human skeletal muscle 2–3 h after a meal , which may represent an adaptive response to improve amino acid intracellular delivery (and consequently enhance the mTORC1 ‘growth’ signal) during this anabolic phase of the dietary cycle . The time course of such responses is a contributory factor underlying the advice [1,48] that protein should be evenly distributed between meals for optimal utilization: three meals containing approximately 30 g protein (15 g EAA) each per day are recommended for adults [1,48]. Amino acid supply may become an increasingly limiting factor for tissue protein synthesis during periods of rapid cell growth or proliferation (e.g. for lymphocytes during an immune response), when intracellular availability of both EAA (e.g. leucine for protein synthesis) and NEAA (e.g. glutamine or glycine for cell metabolism) may become highly dependent on the amino acid transport capacity at the cell surface and sustained growth may therefore require substantial up-regulation of amino acid transporter expression. Growth factor-stimulated up-regulation of nutrient transporter expression may actually drive cellular metabolism in oncogenesis . Genetic or functional inactivation of various amino acid transporters inhibits rapid growth and proliferation of mammalian cells in culture (e.g. [35,36,45▪]) and the system L (LAT1) transporter in particular is viewed as an immunosuppressive  and antitumour  target. Amino acid transport at the cell surface may also be increased for scavenging purposes during periods of amino acid deprivation, a process known as ‘adaptive regulation’ which is exemplified by SNAT2 and involves transcriptional up-regulation of transporter gene expression (downstream of GCN2, via translational up-regulation of the ATF4 transcription factor which binds amino acid-response elements in target genes) and increased stability of the amino acid transport proteins themselves (e.g. [51,52]).
The realization that amino acids (especially EAAs such as Leu) are required for full activation of mTORC1 signalling downstream of insulin and other growth factors has prompted numerous recent studies on the possible use of dietary leucine as an adjunct treatment for insulin resistance related to obesity (e.g. [53▪▪,54]). In this context, the relationship between amino acid transporter function and insulin action in vivo requires closer scrutiny. B0AT-null mice (which display dysregulated nutrient signalling indicative of epithelial EAA starvation) show reduced insulin responsiveness and impaired body weight control [55▪]. Similarly, our ongoing studies in mice (Poncet et al., unpublished observations) indicate that functional activity of the LAT1 leucine transporter in skeletal muscle is an important determinant of baseline insulin sensitivity. These new observations highlight the potential importance of amino acid transport activity to endocrine control of metabolism. Ceramide sphingolipids, which are putative mediators of the progression of insulin target tissues to an insulin-resistant phenotype in response to high saturated-fat diet, induce a marked down-regulation of amino acid transporters in mammalian cells [56,57] and a corresponding reduction in cellular protein synthesis . Such deleterious effects may need to be prevented or bypassed if nutritional interventions such as oral leucine delivery are to be effective in reducing insulin resistance.
Recent research has revealed important roles for amino acid transporters in sensing, as well as delivering, tissue nutrient supplies. It has also provided a clearer understanding of the pathophysiology of amino acid transport defects. New opportunities for nutritional therapy lie in harnessing the potential of ‘nutrient-sensing’ amino acid transporters as targets to promote protein-anabolic signals and improving our understanding of the mechanisms by which amino acid-absorptive capacity is regulated. The rewards for success may include the development of new or improved nutritional approaches designed to retain lean tissue mass and gastrointestinal function on ageing or regain it during rehabilitation from disease or injury.
We thank Dr Pilar Lostao (University of Navarra, Spain) and Dr Graham Christie for valuable discussions.
Conflicts of interest
P.M.T. acknowledges funding from The Wellcome Trust, Biotechnology and Biological Sciences Research Council UK, National Institutes of Health USA and the Rural and Environmental Science and Analytical Services (RESAS) of The Scottish Government.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
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Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 115).
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