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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.

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Current Opinion in Clinical Nutrition and Metabolic Care: January 2013 - Volume 16 - Issue 1 - p 57-65
doi: 10.1097/MCO.0b013e32835a885c
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The recommended daily allowance (RDA) for dietary protein intake by an adult person is 0.8 g/kg/day, irrespective of overall energy intake [1], 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) [6]] 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).

Table 1
Table 1:
The principal gene families of amino acid (AA) transporters expressed in mammalian cells
(a) The sequential relationship between primary, secondary and tertiary active transport systems (denoted I, II and III, respectively) contributing to amino acid (AA) transport across cell membranes. Energy input is provided through ATP hydrolysis by the Na+ pump (primary active transport). Note the operation of symport (co-transport) and antiport (exchange) mechanisms in series downstream of the Na+ pump, illustrated using representative AA transporters (see Table 1 for further information on AA transporter types, mechanism and substrate range). Transport systems I, II and III may be localized to different membrane surfaces in a polarized cell, as illustrated in subpart (b). (b) The principal absorptive AA and peptide transport systems of the intestinal epithelium (see [2] for detailed review and Table 1 for description of systems). The major luminal transport systems for neutral AA are the Na+ coupled transporters B0AT1 and ASCT2. Unlike B0AT1, ASCT2 (not shown in the Figure) is an AA antiporter which does not mediate net movement of AA across epithelial membranes. The major cationic AA transporter at the luminal membrane is b0,+AT. There are additional transporters for anionic AA (EAAT3), proline (PAT1, IMINO) and glycine (PAT1) (not all shown in the Figure). AA antiporters (notably LAT2, y+LAT1) predominate at the basolateral membrane, enabling physiologically useful AA exchanges which, in general, are osmotically neutral [3]. TAT1 and LAT4 are candidate transporters for facilitative neutral AA transport at the intestinal basolateral membrane, although they do not seem to be sufficient for complete net absorption. The molecular identity of the basolateral peptide efflux mechanism is not established. Note the cycling of neutral AA at both membranes as part of the mechanism to absorb cationic AA through AA antiporters (b0,+AT, y+LAT1).
Box 1
Box 1:
no caption available

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.


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 [10] and cystinuria [11] 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) [13]. 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 [14]. 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 [15].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 [16]. 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 [17] and ASCT2 [18] 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 [19]. EGF and growth hormone also prevent the loss of ASCT2 gene expression in resected small intestine [20]. Leptin, a key satiety signalling molecule, positively regulates PepT1 expression and transport capacity in the intestine when secreted into the gut lumen [21]. 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 [24]. 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.


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. [27] 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 [37]. 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. [41] for a ‘classical’ functional review and [42] 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 [36]. 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 [44] 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).

This schematic diagram shows the relationship between amino acid (AA) transport, intracellular AA concentration and the mTORC1 growth signalling pathway in mammalian cells. AA flux values (g/day) are based on whole-body data for a typical adult male [40]. Activation of mTORC1 stimulates protein synthesis and ribosome biogenesis downstream of nutrient (AA) and growth factor (insulin) signals [31,32]. Proteins linking the mTORC1 and vATPase polypeptide complexes are omitted for clarity (see [39▪▪] for details). mTOR, mammalian target of rapamycin; vATPase, vacuolar H+-ATPase.

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 [47], 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 [48]. 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 [49]. 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 [35] and antitumour [50] 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 [57]. 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.


Papers of particular interest, published within the annual period of review, have been highlighted as:

  • ▪ of special interest
  • ▪▪ of outstanding interest

Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 115).


1. Layman D. Dietary Guidelines should reflect new understandings about adult protein needs. Nutr Metab 2009; 6:12.
2. Bröer S. Amino acid transport across mammalian intestinal and renal epithelia. Physiol Rev 2008; 88:249–286.
3. Verrey F, Closs EI, Wagner CA, et al. CATs and HATs: the SLC7 family of amino acid transporters. Pflugers Arch 2004; 447:532–542.
4. Mackenzie B, Erickson JD. Sodium-coupled neutral amino acid (System N/A) transporters of the SLC38 gene family. Pflugers Arch 2004; 447:784–795.
5▪▪. Bröer S, Palacin M. The role of amino acid transporters in inherited and acquired diseases. Biochem J 2011; 436:193–211.

This is an authorative review of amino acid transport disorders, including up-to-date information on biology, genetics and nutritional implications.

6. Taylor PM, Ritchie JW. Tissue uptake of thyroid hormone by amino acid transporters. Best Pract Res Clin Endocrinol Metab 2007; 21:237–251.
7▪. Edwards N, Anderson CMH, Gatfield KM, et al. Amino acid derivatives are substrates or nontransported inhibitors of the amino acid transporter PAT2 (slc36a2). Biochim Biophys Acta 2011; 1808:260–270.

Thorough investigation of amino acid substrate recognition requirements for one of the PAT family of amino acid transporters suggested to be involved in amino acid sensing.

8. Gilbert ER, Wong EA, Webb KE. Peptide absorption and utilization: implications for animal nutrition and health. J Anim Sci 2008; 86:2135–2155.
9. Nakashima EMN, Kudo A, Iwaihara Y, et al. Application of 13C stable isotope labeling liquid chromatography–multiple reaction monitoring–tandem mass spectrometry method for determining intact absorption of bioactive dipeptides in rats. Anal Biochem 2011; 414:109–116.
10. Bröer S. The role of the neutral amino acid transporter B0AT1 (SLC6A19) in Hartnup disorder and protein nutrition. IUBMB Life 2009; 61:591–599.
11. Claes DJ, Jackson E. Cystinuria: mechanisms and management. Pediatr Nephrol 2012; 27:2031–2038.
12▪. Ogier de Baulny H, Schiff M, Dionisi-Vici C. Lysinuric protein intolerance (LPI): a multi organ disease by far more complex than a classic urea cycle disorder. Mol Genet Metab 2012; 106:12–17.

A timely current review of the complex clinical phenotype of this amino acid transport disorder, including discussion and advice on nutritional approaches to treatment.

13. Diamond J, Hammond K. The matches, achieved by natural selection, between biological capacities and their natural loads. Experientia 1992; 48:551–557.
14. Hirst BH. Dietary regulation of intestinal nutrient carriers. Proc Nutr Soc 1993; 52:315–324.
15. Nässl AM, Rubio-Aliaga I, Fenselau H, et al. Amino acid absorption and homeostasis in mice lacking the intestinal peptide transporter PEPT1. Am J Physiol Gastrointest Liver Physiol 2011; 301:G128–137.
16. Hu Y, Smith DE, Ma K, et al. Targeted disruption of peptide transporter Pept1 gene in mice significantly reduces dipeptide absorption in intestine. Mol Pharm 2008; 5:1122–1130.
17. Bhavsar SK, Hosseinzadeh Z, Merches K, et al. Stimulation of the amino acid transporter SLC6A19 by JAK2. Biochem Biophys Res Commun 2011; 414:456–461.
18. Avissar NE, Sax HC, Toia L. In human entrocytes, GLN transport and ASCT2 surface expression induced by short-term EGF are MAPK, PI3K, and Rho-dependent. Dig Dis Sci 2008; 53:2113–2125.
19. Huang Q, Li N, Zhu W, et al. Glutamine transporter ASCT2 was down-regulated in ischemic injured human intestinal epithelial cells and reversed by epidermal growth factor. J Parenter Enteral Nutr 2007; 31:86–93.
20. Avissar NE, Ziegler TR, Toia L, et al. ATB0/ASCT2 expression in residual rabbit bowel is decreased after massive enterectomy and is restored by growth hormone treatment. J Nutr 2004; 134:2173–2177.
21. Yarandi SS, Hebbar G, Sauer CG, et al. Diverse roles of leptin in the gastrointestinal tract: modulation of motility, absorption, growth, and inflammation. Nutrition 2011; 27:269–275.
22. Ducroc R, Sakar Y, Fanjul C, et al. Luminal leptin inhibits l-glutamine transport in rat small intestine: involvement of ASCT2 and B0AT1. Am J Physiol Gastrointest Liver Physiol 2010; 299:G179–G185.
23▪. Fanjul C, Barrenetxe J, Inigo C, et al. Leptin regulates sugar and amino acids transport in the human intestinal cell line Caco-2. Acta Physiol (Oxf) 2012; 205:82–91.

This study shows that apical (luminal) application of leptin rapidly down-regulates amino acid transport at the apical membrane of intestinal cells by a mechanism that involves reducing surface expression of amino acid transporters.

24. Mourad FH, Barada KA, Khoury C, et al. Amino acids in the rat intestinal lumen regulate their own absorption from a distant intestinal site. Am J Physiol Gastrointest Liver Physiol 2009; 297:G292–G298.
25. Camargo SMR, Singer D, Makrides V, et al. Tissue-specific amino acid transporter partners ACE2 and collectrin differentially interact with Hartnup mutations. Gastroenterology 2009; 136:872–882.e873.
26▪. Fairweather SJ, Bröer A, O’Mara ML, Bröer S. Intestinal peptidases form functional complexes with the neutral amino acid transporter B0AT1. Biochem J 2012; 446:135–148.

A fascinating new study which demonstrates a functional interaction between a digestive enzyme (aminopeptidase N) and B0AT1 to produce an absorption-enhancing metabolon at the luminal (brush-border) membrane of the small intestine.

27. Brosnan JT. Interorgan amino acid transport and its regulation. J Nutr 2003; 133:2068S–2072S.
28. He Y, Hakvoort TB, Kohler SE, et al. Glutamine synthetase in muscle is required for glutamine production during fasting and extrahepatic ammonia detoxification. J Biol Chem 2010; 285:9516–9524.
29. Karinch AM, Lin CM, Meng Q, et al. Glucocorticoids have a role in renal cortical expression of the SNAT3 glutamine transporter during chronic metabolic acidosis. Am J Physiol Renal Physiol 2007; 292:F448–455.
30. Baird FE, Beattie KJ, Hyde AR, et al. Bidirectional substrate fluxes through the System N (SNAT5) glutamine transporter may determine net glutamine flux in rat liver. J Physiol 2004; 559:367–381.
31. Kimball SR, Jefferson LS. Control of translation initiation through integration of signals generated by hormones, nutrients, and exercise. J Biol Chem 2010; 285:29027–29032.
32. Avruch J, Long X, Ortiz-Vega S, et al. Amino acid regulation of TOR complex 1. Am J Physiol Endocrinol Metab 2009; 296:E592–602.
33. Hundal HS, Taylor PM. Amino acid transceptors: gate keepers of nutrient exchange and regulators of nutrient signaling. Am J Physiol Endocrinol Metab 2009; 296:E603–E613.
34. Nicklin P, Bergman P, Zhang B, et al. Bidirectional transport of amino acids regulates mTOR and autophagy. Cell 2009; 136:521–534.
35. Usui T, Nagumo Y, Watanabe A, et al. Brasilicardin A, a natural immunosuppressant, targets amino acid transport System L. Chem Biol 2006; 13:1153–1160.
36. Heublein S, Kazi S, Ogmundsdottir MH, et al. Proton-assisted amino-acid transporters are conserved regulators of proliferation and amino-acid-dependent mTORC1 activation. Oncogene 2010; 29:4068–4079.
37. Sonenberg N, Hinnebusch AG. Regulation of translation initiation in eukaryotes: mechanisms and biological targets. Cell 2009; 136:731–745.
38▪. Han JM, Jeong SJ, Park MC, et al. Leucyl-tRNA synthetase is an intracellular leucine sensor for the mTORC1-signaling pathway. Cell 2012; 149:410–424.

The first study to clearly identify a leucine-binding protein upstream of the nutrient-sensitive mTORC1 pathway.

39▪▪. Zoncu R, Bar-Peled L, Efeyan A, et al. mTORC1 senses lysosomal amino acids through an inside-out mechanism that requires the vacuolar H+-ATPase. Science 2011; 334:678–683.

An elegant experimental investigation of lysosomal involvement in intracellular amino acid sensing upstream of mTORC1. A combination of proteomic and gene overexpression /knockdown approaches identifies vATPase as an unexpected key component of the sensing-signalling mechanism and PAT1 as a potential negative modifier.

40. Waterlow JC. Whole-body protein turnover in humans: past, present, and future. Annu Rev Nutr 1995; 15:57–92.
    41. Pisoni RL, Thoene JG. The transport systems of mammalian lysosomes. Biochim Biophys Acta 1991; 1071:351–373.
    42. Liu B, Du H, Rutkowski R, et al. LAAT-1 is the lysosomal lysine/arginine transporter that maintains amino acid homeostasis. Science 2012; 337:351–354.
    43. Thwaites DT, Anderson CMH. The SLC36 family of proton-coupled amino acid transporters and their potential role in drug transport. Br J Pharmacol 2011; 164:1802–1816.
    44. Korolchuk VI, Saiki S, Lichtenberg M, et al. Lysosomal positioning coordinates cellular nutrient responses. Nat Cell Biol 2011; 13:453–460.
    45▪. Pinilla J, Aledo JC, Cwiklinski E, et al. SNAT2 transceptor signalling via mTOR: a role in cell growth and proliferation? Front Biosci (Elite Ed) 2011; 3:1289–1299.

    The latest evidence supporting the concept of mammalian amino acid transporters as dual-function ‘nutrient transceptors’.

    46▪▪. Gietzen DW, Aja SM. The brain's response to an essential amino acid-deficient diet and the circuitous route to a better meal. Mol Neurobiol 2012; 46:332–348.

    Excellent and timely review of our current knowledge of the central mechanisms underlying food-choice behaviour with respect to protein quality. It provides a coherent, integrative summary of recent advances in our understanding of molecular, anatomical and neurophysiological aspects of this complex process.

    47. Drummond MJ, Glynn EL, Fry CS, et al. An increase in essential amino acid availability upregulates amino acid transporter expression in human skeletal muscle. Am J Physiol Endocrinol Metab 2010; 298:E1011–E1018.
    48. Paddon-Jones D, Rasmussen BB. Dietary protein recommendations and the prevention of sarcopenia. Curr Opin Clin Nutr Metab Care 2009; 12:86–90.
    49. Edinger AL. Controlling cell growth and survival through regulated nutrient transporter expression. Biochem J 2007; 406:1–12.
    50. Oda K, Hosoda N, Endo H, et al. L-type amino acid transporter 1 inhibitors inhibit tumor cell growth. Cancer Sci 2010; 101:173–179.
    51. Palii SS, Thiaville MM, Pan Y-X, et al. Characterization of the amino acid response element within the human sodium-coupled neutral amino acid transporter 2 (SNAT2) System A transporter gene. Biochem J 2006; 395:517–527.
    52. Hyde R, Cwiklinski EL, MacAulay K, et al. Distinct sensor pathways in the hierarchical control of SNAT2, a putative amino acid transceptor, by amino acid availability. J Biol Chem 2007; 282:19788–19798.
    53▪▪. Macotela Y, Emanuelli B, Bang AM, et al. Dietary leucine: an environmental modifier of insulin resistance acting on multiple levels of metabolism. PLoS ONE 2011; 6:e21187.

    Wide-ranging investigation of metabolomic profile, gene expression and insulin signalling in tissues of mice given oral leucine supplementation on normal or high-fat diets. The results indicate that modest changes in leucine consumption may have substantial systemic effects tending to counteract development of a high-fat metabolic syndrome.

    54. Adeva MM, Calvino J, Souto G, Donapetry C. Insulin resistance and the metabolism of branched-chain amino acids in humans. Amino Acids 2012; 43:171–181.
    55▪. Bröer A, Juelich T, Vanslambrouck JM, et al. Impaired nutrient signaling and body weight control in a Na+-neutral amino acid cotransporter (Slc6a19)-deficient mouse. J Biol Chem 2011; 286:26638–26651.

    Phenotypic study of B0AT1-null mice which reveals defects in epithelial amino acid signalling and whole-body insulin action.

    56. Guenther GG, Peralta ER, Rosales KR, et al. Ceramide starves cells to death by downregulating nutrient transporter proteins. Proc Natl Acad Sci U S A 2008; 105:17402–17407.
    57. Hyde R, Hajduch E, Powell DJ, et al. Ceramide down-regulates System A amino acid transport and protein synthesis in rat skeletal muscle cells. FASEB J 2005; 19:461–463.

    absorption; mTORC1 pathway; nutrient signalling; transceptor

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