Journal of Thyroid Research

Journal of Thyroid Research / 2010 / Article

Research Article | Open Access

Volume 2010 |Article ID 726098 |

Fiona E. Mitchell, Lisa A. Roy, Peter M. Taylor, "Iodothyronine Interactions with the System L1 Amino Acid Exchanger in 3T3-L1 Adipocytes", Journal of Thyroid Research, vol. 2010, Article ID 726098, 8 pages, 2010.

Iodothyronine Interactions with the System L1 Amino Acid Exchanger in 3T3-L1 Adipocytes

Academic Editor: Masanobu Yamada
Received08 Dec 2009
Revised30 Mar 2010
Accepted04 May 2010
Published24 Jun 2010


Thyroid hormones enter isolated white adipocytes largely by a System L1-type amino acid transporter en route to exerting genomic actions. Differentiated 3T3-L1 mouse adipocytes in culture express mRNA for LAT1 (the catalytic subunit of high-affinity System L1). L-[125I]-T3 uptake into 3T3-L1 adipocytes included a substantial saturable component inhibited by leucine. L-[3H]phenylalanine uptake into 3T3-L1 cells was saturable ( of 31  M), competitively inhibited by T3 ( of 1.2  M) and blocked by leucine, BCH, and rT3 as expected for substrate interactions of System L1. Efflux of preloaded L-[3H]phenylalanine from 3T3-L1 adipocytes was trans stimulated by external leucine, demonstrating the obligatory exchange mechanism of System L1 transport. T3 (10 M) did not significantly trans stimulate L-[3H]phenylalanine efflux, but did competitively inhibit the trans stimulatory effect of 10 M leucine. The results highlight strong competitive interactions between iodothyronines (T3, rT3) and amino acids for transport by System L1 in adipocytes, which may impact cellular iodothyronine exchanges during altered states of protein nutrition.

1. Introduction

The thyroid hormones (THs) L-thyroxine and L-triiodothyronine are iodothyronines exerting their major physiological effects by regulation of gene expression in target cells, which they must first enter by crossing the plasma membrane [13]. Iodothyronines are now known to translocate cell membranes by a variety of mechanisms, which include the sharing of transport systems for large neutral amino acids (LNAAs; principally aromatic and branched-chain amino acids) and organic anions (see, e.g., [46] for review). TH retain a tyrosine-derived amino acid moiety within the iodothyronine molecular structure, allowing them to be accepted as substrates by LNAA transporters such as System L (notably the “System L1” SLC7A5/SLC3A2 heterodimer isoform LAT1) [7, 8] and System T (MCT10; SLC16A10) [9].

White adipose tissue is an important target tissue for TH action, where effects include stimulation of adipogenesis itself [10], modulation of fatty acid synthesis via regulation of expression of lipogenic enzymes [1012] and modulation of leptin secretion [13, 14]. TH enter rat adipocytes largely by a System L1-type amino acid transporter [15] and LAT1 mRNA are expressed in rat adipocytes [16]. System L1 is also likely to be of major importance for amino acid metabolism in adipose tissue, which is a site of significant BCAA degradation and utilization for fatty acid and sterol synthesis [17, 18]. The System L1 substrate leucine in particular appears to be involved in modulation of the mTOR signalling pathway in adipocytes [19]. The activity and expression of System L1 in adipocytes, and its regulation by TH, may therefore be of quantitative importance for whole body iodothyronine and amino acid turnover. In the present study using differentiated 3T3-L1 mouse adipocytes [20, 21], we investigate how the mechanism of System L1 transport is influenced by iodothyronines.

2. Experimental Procedures

2.1. Materials

L-[2,3,4,5,6-3H]Phenylalanine was obtained from Amersham (GE Healthcare, Slough, U.K.) and L-[125I]-Triiodothyronine from PerkinElmer (Bucks, UK). Cell culture media were obtained from GibcoBRL Life Technologies (Paisley, UK) unless stated otherwise; other chemicals were obtained from either Sigma Chemicals (Poole, Dorset, UK) or BDH Merck Ltd (Poole, Dorset, UK).

2.2. Cell Culture

3T3-L1 mouse fibroblasts (ATCC CL-173) were cultured at 3 C, 95% air: 5% CO2 in Dulbecco’s Modified Eagles Medium (DMEM; high-glucose) with 10% Donor Bovine Serum (DBS) and 1% antibiotic/antimycotic (A/A) solution. Before reaching confluence, cells were resuspended by trypsinisation and reseeded into 6- or 12-well experimental plates. To differentiate into adipocytes [22], the 3T3-L1 fibroblasts were grown to confluence (preadipocytes) and then the medium was changed to DMEM with 10% foetal bovine serum (FBS) and 1% A/A solution over the duration of the differentiation process. For the first two days of differentiation, 1  g mL-1 insulin, 5  M isobutylmethylxanthine, and 100 pM dexamethasone were also added to the media and for the subsequent two days 1  g mL-1 insulin alone was added. The adherent cells were allowed to fully differentiate over a further six days, then used for experiments on days 11 or 12.

2.3. [125I]-T3 and [3H]Phenylalanine Uptakes

Immediately prior to an experiment, media was aspirated from the wells and the cells were washed twice in PBS. Transport buffer (121 mM NaCl, 4.9 mM KCl, 2.5 mM MgSO4, 20 mM Tris-HCl, 1 mM CaCl2, pH 7.4) containing either L-[125I]-T3 at 30 kBq mL-1 or L-[3H]phenylalanine at 18.5 kBq mL-1 and any other necessary compounds (e.g., inhibitors) were then added to the cells. Once the cells had been incubated in the transport buffer for the designated time period, the buffer was aspirated and the cells were washed quickly three times in cold PBS to halt the uptake process. The cells were then lysed in 1.25 mL 50 mM NaOH overnight at room temperature prior to assay of radioactivity by liquid scintillation counting and determination of protein concentration using Bradford reagent (Biorad UK). Preliminary experiments (data not shown) demonstrated that the uptake of 5  M [3H]phenylalanine was linear for at least 5 minutes and therefore, in all subsequent experiments reported here, phenylalanine uptake was measured over a 3-minute period. L-[125I]-T3 uptakes were measured over a 10-minute period [15]. The specific activity (DPM pmol-1) of radiotracers was calculated from the radioactivity (DPM) of 10  L transport buffer measured using liquid scintillation counting; tracer uptake is expressed as pmol mg protein-1 10 min. For trans stimulation studies, 3T3-L1 adipocytes were preincubated in transport buffer containing 2 mM leucine for 15 min prior to the initial PBS washes.

2.4. [3H]Phenylalanine Efflux

3T3-L1 cells were preloaded with [3H]phenylalanine for a period of 15 minutes according to the uptake protocol described above. The radioactive buffer was then aspirated off and the cells were rapidly washed three times with PBS. The cells were then re-incubated in (nonradioactive) transport buffer, half of which was removed at timed intervals and immediately replenished with fresh buffer. At the end of each experiment, the remaining buffer was aspirated and the cells lysed overnight in 1.25 mL 50 mM NaOH. The incubation buffer aliquots and cell lysates were assayed for radioactivity and the lysate also for protein concentration as described above.

2.5. RNA Extraction and RT-PCR

RNA was extracted from cells using TRIzol Reagent (Invitrogen, Poole, UK) according to the manufacturer’s instructions, resuspended in RNase-free H2O and quantified by UV spectrometry. 1  g RNA was denatured in the presence of 0.5  g OligodT (Oligo Synthesis Service, University of Dundee) at 7 C for 5 min then reverse-transcribed using Moloney Murine Leukemia Virus Reverse Transcriptase (M-MLV RT) at 100 U/ g RNA in 25  L reaction buffer including 500  M dNTPs (Fermentas) at 4 C for 1 hour. The resulting first-strand cDNA was stored at 2 C prior to use in PCR using gene-specific primers to test for specific mRNA expression. The primer sets used in the PCR program were LAT1 forward  -tctccttgcccattgtcacc-     reverse     -atgactcccaggtggtagttcc- LAT2 forward  -aagggaacccgacagcgaaacaac-     reverse     -gggggaagcaggtagggaagagtg- .

For each PCR, 2  L of first strand DNA, 1  M each primer and standard 2x GoTaq Green PCR Master Mix (Promega) were used in a 20  L total volume. The PCR programme used was 9 C, 3 min; [9 C, 30 s; 5 C, 30 s; 7 C, 1 min] 40 cycles; 7 C, 2 min using a Thermo Scientific Hybaid Px2 thermal cycler.

2.6. Data Analysis

The data are expressed as means S.E.M for adipocyte preparations. Statistical significance for uptake measurements was assessed by one-way ANOVA followed by a Dunnet post hoc test. For efflux measurements, Graphpad software (San Diego, CA, USA) was used to determine whether the gradients of the lines of best fit (rate constants) were significantly different from control. Differences were considered significant where .

3. Results

3.1. L-T3 Uptake

The uptake of 50 nM L-[125I]-T3 into 3T3-L1 adipocytes included a substantial saturable component, being reduced by around 40% on addition of 10 uM unlabelled T3 (Figure 1). The magnitude of this saturable component (approximately 1–1.2 pmol mg protein-1 10 min-1) was similar in both adipocytes and pre-adipocytes, although total uptake was about 50% higher in pre-adipocytes. An excess of the LNAA leucine (10 mM), inhibited over 80% of saturable T3 uptake (Figure 1). Pre-incubation of 3T3-L1 adipocytes in transport buffer containing 2 mM leucine for 15 minutes (followed by a rapid wash in PBS) resulted in a minor trans stimulatory increase in saturable 50 nM L-[125I]-T3 uptake (by 20 8.5%, ), although this increase did not reach statistical significance.

3.2. Phenylalanine Uptake

The uptake of 5  M phenylalanine into 3T3-L1 cells (0.465 0.065 nmol mg protein-1 min-1, ) was saturable, being reduced more than 95% by addition of excess (10 mM) unlabelled phenylalanine, leucine or BCH (2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid; a synthetic System L-type amino acid transport inhibitor) (Figure 2). 5  M phenylalanine uptake was also substantially inhibited by T3 and rT3 (82% and 57% inhibition, resp.) at 10  M, although inhibition by T4 (17%) and triiodothyroacetic acid (TRIAC; a T3 analogue lacking the α-amino grouping) did not achieve statistical significance at this concentration (Figure 2). Saturable phenylalanine uptake into 3T3-L1 cells had a of 31  M and a of 2.6 0.5 nmol mg protein-1 min-1 (mean sem, ; see Figure 3). The inhibitory effect of T3 on phenylalanine uptake also appeared to be competitive, with a of the order of 1-2  M (see Figure 4).

3.3. Phenylalanine Efflux

Semilogarithmic plots of the cumulative loss of preloaded [3H]phenylalanine tracer from 3T3-L1 cells showed that the initial efflux was described by a single rate constant (see Figure 5(a)), indicating that phenylalanine was released largely from a single, freely exchangeable intracellular pool. Efflux of pre-loaded L-[3H]phenylalanine from 3T3-L1 adipocytes was trans stimulated in a concentration-dependent manner by external leucine (Figure 5(a)). Leucine and tryptophan (both System L substrates) were able to generate over 20 times stimulation of basal phenylalanine efflux (Figure 5(b)). T3 is known to be a substrate for System L1 amino acid transport, so we investigated the ability of T3 to trans stimulate phenylalanine efflux. T3 was unable to significantly trans stimulate L-[3H]phenylalanine efflux at 10  M (a concentration approaching the limit of T3 solubility in culture medium), although it did inhibit the trans stimulatory effect of 10  M leucine (see Figure 6(a)). rT3 also inhibited the trans stimulatory effect of 10  M leucine, although T4 did not to any significant degree (Figure 6(a)). The T3 analogue TRIAC (which does not interact with System L1) had no effect on either basal or leucine-stimulated phenylalanine efflux. The effect of T3 upon leucine trans stimulated phenylalanine efflux was found to be concentration dependent (see Figure 6(b)) with 3.2  M T3 able to inhibit 50% of 10  M leucine trans stimulated phenylalanine efflux, demonstrating the relatively high affinity of T3 for this interaction.

3.4. Transporter mRNA Expression

We detected mRNA for LAT1, but not LAT2 (the alternative catalytic subunit producing System L1-type amino acid transport) in 3T3-L1 cells using RT-PCR (see Figure 7).

4. Discussion

3T3-L1 cells in culture are used extensively as an in vitro model system for studying white adipose tissue [21] and the present results demonstrate that saturable uptake of the thyroid hormone L-T3 in both pre-adipocytes and terminally differentiated 3T3-L1 adipocytes occurs largely by a mechanism inhibited by the LNAA leucine, a substrate of the multifunctional System L1 transport system shared by LNAA and iodothyronines (see [6] for review). Saturable uptake processes appear to be the predominant routes of cellular TH entry for genomic signaling via thyroid receptors in animal cells [7]. There appears to be little change in functional expression of saturable T3 transport during adipocyte differentiation (at least for 3T3-L1 cells), which is perhaps unsurprising given that T3 is important for the differentiation process itself as well as the control of mature adipocyte functions [10]. The nonsaturable “uptake” of T3 into adipocytes includes surface binding (presumably to secreted lipids and lipoproteins) and partitioning into the lipid bilayer as well as passive diffusion into the cytosol [15]. Transport of phenylalanine (a representative LNAA substrate for Systems L1, L2 and T) in 3T3-L1 adipocytes conforms almost exclusively with “classical” System L1-type function as mediated by LAT1 [23], in that (i) phenylalanine influx has a in the low micromolar range (31  M), (ii) it is inhibited by BCH and (iii) phenylalanine efflux is markedly trans stimulated in a concentration-dependent manner by both leucine and tryptophan (consistent with the obligatory exchange mechanism of System L1 [24]). These features are clearly distinct from those of other likely contributors to phenylalanine transport, specifically because (i) System L2 (LAT3/LAT4) does not recognize tryptophan as a substrate [25, 26], (ii) System T (MCT10, originally named TAT1) does not recognize leucine as a substrate [27, 28], and (iii) LAT3, LAT4, and MCT10 all utilise facilitative diffusion rather than an exchange mechanism [2527]. Phenylalanine uptake by 3T3-L1 cells was competitively inhibited by T3 ( of 1-2  M) and rT3 in a manner consistent with expected substrate interactions for the LAT1 System L1 transporter [2932]. This strong competitive interaction between iodothyronines and LNAA for transport by System L1 in 3T3-L1 mouse adipocytes is consistent with our previous studies using isolated white adipocytes from rats [15], although the relatively-weak inhibitory effects of T4 in the present study may reflect minor species-specific differences in the relative affinity of different TH for LAT1. The for phenylalanine transport in 3T3-L1 cells (2.6 nmol mg protein-1 min-1) is broadly equivalent to 50 pmol 105 cells-1 min-1, a value of the same order of magnitude as that measured for System L1 transport in rat adipocytes [15].

Collectively, our results indicate that the Na+-independent System L1 transporter contributes substantially to iodothyronine and LNAA transport in 3T3-L1 adipocytes and thus for delivery of TH from the plasma to the cytosol, where ultimately they reach the cell nucleus. System L1 has been shown to be an important effector of T3 transport in tissues including placenta and brain as well as adipose ([6] for review). The LAT1 and LAT2 genes encode for alternative catalytic protein subunits of System L1 and these function as heterodimers with 4F2hc/CD98 (see [23] for review). LAT1 and LAT2 both mediate uptake of iodothyronines as well as LNAA [30, 31] but while both are expressed in rat adipocytes [16], it appears that only LAT1 is expressed at the mRNA level in 3T3-L1 cells. Our transport studies also indicate the predominant functional expression of LAT1 in 3T3-L1 cells. The values obtained for iodothyronine transport by System L1 are substantially lower than those measured for LNAA transport, which help T3 especially to compete effectively with amino acids for transport under physiological conditions (see [6] for review). High-affinity receptors for both T4 and T3 have been identified associated with the plasma membrane of adipocytes [33] and these may also facilitate preferential iodothyronine uptake [15]. To our knowledge, T3 is the most potent natural inhibitor of System L1 in the mammalian body (and easily surpasses the widely-used synthetic inhibitor BCH in terms of , if not specificity), although Brasilicardin compounds isolated from bacteria have recently been shown to inhibit with nanomolar potency [34]. Given the therapeutic potential of System L1 inhibitors as immunosuppressants and anticancer drugs [34, 35], it is tempting to suggest that the iodothyronine skeleton might be used as a template for improved design of highly specific, non-TH active, System L1 inhibitors. Reverse T3 but not TRIAC (a T3 analog lacking an amino acid moiety which acts as a potent thyroid receptor agonist) interacts with System L1 in adipocytes, demonstrating structural specificity of System L1 which is clearly distinct from that of nuclear thyroid hormone receptors. TRIAC selectively stimulates the metabolic rate of adipose tissue in vivo, a feature considered as a potential tool to increase whole body energy metabolism [13]. It appears from our results that TRIAC enters adipocytes by a different mechanism to T3, which may help explain why TRIAC administered to rats accumulates in white adipose tissue even when coadministered with high T3 doses [13].

The bulky T3 molecule has a much reduced for transport by System L1 compared to LNAA [30], such that its specific interactions with System L1 transport may competitively inhibit not only influx but efflux of substrate LNAA by retarding conformational changes of the transport cycle (note the inhibitory action of T3 on leucine-induced trans stimulation of phenylalanine efflux in 3T3-L1 cells). Nevertheless, the obligatory exchange mechanism of the System L1 transporter should allow limited LNAA–iodothyronine or T4-T3/rT3 exchanges across the adipocyte plasma membrane and we indeed observed a minor trans stimulation of saturable L-T3 uptake in 3T3-L1 adipocytes preincubated with leucine. It is noteworthy in this respect that adipose tissue in vivo releases small quantities of LNAA [36]. White adipose tissue depots have the capacity to deiodinate iodothyronines (especially rT3) [37, 38], thus it is conceivable that regulation of iodothyronine turnover in fat cells through this pathway would contribute significantly to modulation of whole body T4-rT3 metabolism, perhaps particularly in obese individuals. In this respect, downregulation of iodothyronine uptake by System L1 in adipocytes in the hypothyroid state, as reported previously in adipocytes from hypothyroid rats [15], would tend to reduce the sensitivity of adipose tissue to hormonal activation but might help conserve hormone and iodine availability to other tissues by reducing their degradation in adipose tissue. Physiological variations in plasma LNAA concentrations, as occurs during natural feeding cycles, may impact TH transport and action in adipose (and other tissues where System L1 is the predominant TH transporter).


BCAA:Branched chain amino acids
BCH:2-amino [ ,2,1] heptane–2-carboxylic acid
rT3:Reverse L-triiodothyronine
TH:thyroid hormone
TRIAC:triiodothyroacetic acid.


This paper was supported by the UK BBSRC (FEM) and UK Physiological Society (LAR). The 3T3-L1 cells were a gift from Eric Hajduch, Centre de Recherche des Cordeliers, Paris, France.


  1. G. Hennemann, R. Docter, E. C. H. Friesema, M. De Jong, E. P. Krenning, and T. J. Visser, “Plasma membrane transport of thyroid hormones and its role in thyroid hormone metabolism and bioavailability,” Endocrine Reviews, vol. 22, no. 4, pp. 451–476, 2001. View at: Publisher Site | Google Scholar
  2. B. Gereben, A. M. Zavacki, S. Ribich et al., “Cellular and molecular basis of deiodinase-regulated thyroid hormone signaling,” Endocrine Reviews, vol. 29, no. 7, pp. 898–938, 2008. View at: Publisher Site | Google Scholar
  3. P. M. Yen, “Physiological and molecular basis of thyroid hormone action,” Physiological Reviews, vol. 81, no. 3, pp. 1097–1142, 2001. View at: Google Scholar
  4. T. Abe, T. Suzuki, M. Unno, T. Tokui, and S. Ito, “Thyroid hormone transporters: recent advances,” Trends in Endocrinology and Metabolism, vol. 13, no. 5, pp. 215–220, 2002. View at: Publisher Site | Google Scholar
  5. E. C. H. Friesema, J. Jansen, C. Milici, and T. J. Visser, “Thyroid hormone transporters,” Vitamins and Hormones, vol. 70, pp. 137–167, 2005. View at: Publisher Site | Google Scholar
  6. P. M. Taylor and J. W. A. Ritchie, “Tissue uptake of thyroid hormone by amino acid transporters,” Best Practice and Research: Clinical Endocrinology and Metabolism, vol. 21, no. 2, pp. 237–251, 2007. View at: Publisher Site | Google Scholar
  7. J. W. A. Ritchie, Y.-B. Shi, Y. Hayashi et al., “A role for thyroid hormone transporters in transcriptional regulation by thyroid hormone receptors,” Molecular Endocrinology, vol. 17, no. 4, pp. 653–661, 2003. View at: Publisher Site | Google Scholar
  8. J. W. A. Ritchie and P. M. Taylor, “Role of the system L permease LAT1 in amino acid and iodothyronine transport in placenta,” Biochemical Journal, vol. 356, no. 3, pp. 719–725, 2001. View at: Publisher Site | Google Scholar
  9. E. C. H. Friesema, J. Jansen, J.-W. Jachtenberg, W. E. Visser, M. H. A. Kester, and T. J. Visser, “Effective cellular uptake and efflux of thyroid hormone by human monocarboxylate transporter 10,” Molecular Endocrinology, vol. 22, no. 6, pp. 1357–1369, 2008. View at: Publisher Site | Google Scholar
  10. M.-J. Obregon, “Thyroid hormone and adipocyte differentiation,” Thyroid, vol. 18, no. 2, pp. 185–195, 2008. View at: Publisher Site | Google Scholar
  11. N. Pontikides and G. E. Krassas, “Basic endocrine products of adipose tissue in states of thyroid dysfunction,” Thyroid, vol. 17, no. 5, pp. 421–431, 2007. View at: Publisher Site | Google Scholar
  12. B. Blennemann, P. Leahy, T.-S. Kim, and H. C. Freake, “Tissue-specific regulation of lipogenic mRNAs by thyroid hormone,” Molecular and Cellular Endocrinology, vol. 110, no. 1-2, pp. 1–8, 1995. View at: Publisher Site | Google Scholar
  13. G. Medina-Gomez, R. M. Calvo, and M.-J. Obregon, “Thermogenic effect of triiodothyroacetic acid at low doses in rat adipose tissue without adverse side effects in the thyroid axis,” American Journal of Physiology, vol. 294, no. 4, pp. E688–E697, 2008. View at: Publisher Site | Google Scholar
  14. L. Zabrocka, J. Klimek, and J. Swierczynski, “Evidence that triiodothyronine decreases rat serum leptin concentration by down-regulation of leptin gene expression in white adipose tissue,” Life Sciences, vol. 79, no. 11, pp. 1114–1120, 2006. View at: Publisher Site | Google Scholar
  15. J. W. A. Ritchie, C. J. F. Collingwood, and P. M. Taylor, “Effect of hypothyroidism on pathways for iodothyronine and tryptophan uptake into rat adipocytes,” American Journal of Physiology, vol. 280, no. 2, pp. E254–E259, 2001. View at: Google Scholar
  16. J. W. A. Ritchie, F. E. Baird, G. R. Christie et al., “Mechanisms of glutamine transport in rat adipocytes and acute regulation by cell swelling,” Cellular Physiology and Biochemistry, vol. 11, no. 5, pp. 259–270, 2001. View at: Publisher Site | Google Scholar
  17. P. She, C. Van Horn, T. Reid, S. M. Hutson, R. N. Cooney, and C. J. Lynch, “Obesity-related elevations in plasma leucine are associated with alterations in enzymes involved in branched-chain amino acid metabolism,” American Journal of Physiology, vol. 293, no. 6, pp. E1552–E1563, 2007. View at: Publisher Site | Google Scholar
  18. H. M. Goodman and G. P. Frick, “Metabolism of branched-chain amino acids in adipose tissue,” in Metabolism and Clinical Implications of Branched Chain Amino and Ketoacids, A. P. Walser and A. Williams, Eds., Elsevier, Amsterdam, The Netherlands, 1981. View at: Google Scholar
  19. H. L. Fox, P. T. Pham, S. R. Kimball, L. S. Jefferson, and C. J. Lynch, “Amino acid effects on translational repressor 4E-BP1 are mediated primarily by L-leucine in isolated adipocytes,” American Journal of Physiology, vol. 275, no. 5, pp. C1232–C1238, 1998. View at: Google Scholar
  20. M. S. O'Shea Alvarez, “3T3 cells in adipocytic conversion,” Archivos de Investigacion Medica, vol. 22, no. 2, pp. 235–244, 1991. View at: Google Scholar
  21. T. C. Otto and M. D. Lane, “Adipose development: from stem cell to adipocyte,” Critical Reviews in Biochemistry and Molecular Biology, vol. 40, no. 4, pp. 229–242, 2005. View at: Publisher Site | Google Scholar
  22. R. Hyde, G. R. Christie, G. J. Litherland, E. Hajduch, P. M. Taylor, and H. S. Hundal, “Subcellular localization and adaptive up-regulation of the system A (SAT2) amino acid transporter in skeletal-muscle cells and adipocytes,” Biochemical Journal, vol. 355, no. 3, pp. 563–568, 2001. View at: Google Scholar
  23. F. Verrey, E. I. Closs, C. A. Wagner, M. Palacin, H. Endou, and Y. Kanai, “CATs and HATs: the SLC7 family of amino acid transporters,” Pflugers Archiv European Journal of Physiology, vol. 447, no. 5, pp. 532–542, 2004. View at: Publisher Site | Google Scholar
  24. C. Meier, Z. Ristic, S. Klauser, and F. Verrey, “Activation of system L heterodimeric amino acid exchangers by intracellular substrates,” EMBO Journal, vol. 21, no. 4, pp. 580–589, 2002. View at: Publisher Site | Google Scholar
  25. E. Babu, Y. Kanai, A. Chairoungdua et al., “Identification of a novel system L amino acid transporter structurally distinct from heterodimeric amino acid transporters,” Journal of Biological Chemistry, vol. 278, no. 44, pp. 43838–43845, 2003. View at: Publisher Site | Google Scholar
  26. S. Bodoy, L. Martin, A. Zorzano, M. Palacin, R. Estevez, and J. Bertran, “Identification of LAT4, a novel amino acid transporter with system L activity,” Journal of Biological Chemistry, vol. 280, no. 12, pp. 12002–12011, 2005. View at: Publisher Site | Google Scholar
  27. T. Ramadan, S. M. R. Camargo, V. Summa et al., “Basolateral aromatic amino acid transporter TAT1 (Slc16a10) functions as an efflux pathway,” Journal of Cellular Physiology, vol. 206, no. 3, pp. 771–779, 2006. View at: Publisher Site | Google Scholar
  28. D. K. Kim, Y. Kanai, A. Chairoungdua, H. Matsuo, S. H. Cha, and H. Endou, “Expression cloning of a Na+-independent aromatic amino acid transporter with structural similarity to H+/monocarboxylate transporters,” Journal of Biological Chemistry, vol. 276, no. 20, pp. 17221–17228, 2001. View at: Publisher Site | Google Scholar
  29. A. M. Mitchell, K. A. Rowan, S. W. Manley, and R. H. Mortimer, “Comparison of mechanisms mediating uptake and efflux of thyroid hormones in the human choriocarcinoma cell line, JAR,” Journal of Endocrinology, vol. 161, no. 1, pp. 107–113, 1999. View at: Google Scholar
  30. J. W. A. Ritchie, G. J. Peter, Y.-B. Shi, and P. M. Taylor, “Thyroid hormone transport by 4F2hc-IU12 heterodimers expressed in Xenopus oocytes,” Journal of Endocrinology, vol. 163, no. 2, pp. R5–R9, 1999. View at: Google Scholar
  31. E. C. H. Friesema, R. Docter, E. P. C. M. Moerings et al., “Thyroid hormone transport by the heterodimeric human system L amino acid transporter,” Endocrinology, vol. 142, no. 10, pp. 4339–4348, 2001. View at: Publisher Site | Google Scholar
  32. J.-P. Blondeau, A. Beslin, F. Chantoux, and J. Francon, “Triiodothyronine is a high-affinity inhibitor of amino acid transport system L1 in cultured astrocytes,” Journal of Neurochemistry, vol. 60, no. 4, pp. 1407–1413, 1993. View at: Google Scholar
  33. F. Parl, L. Korcek, J. S. Siegel, and M. Tabachnick, “Uptake of triiodothyronine and thyroxine by isolated rabbit adipocytes,” FEBS Letters, vol. 83, no. 1, pp. 145–147, 1977. View at: Publisher Site | Google Scholar
  34. T. Usui, Y. Nagumo, A. Watanabe et al., “Brasilicardin A, a natural immunosuppressant, targets amino acid transport system L,” Chemistry and Biology, vol. 13, no. 11, pp. 1153–1160, 2006. View at: Publisher Site | Google Scholar
  35. P. Nicklin, P. Bergman, B. Zhang et al., “Bidirectional transport of amino acids regulates mTOR and autophagy,” Cell, vol. 136, no. 3, pp. 521–534, 2009. View at: Publisher Site | Google Scholar
  36. T. J. Kowalski, G. Wu, and M. Watford, “Rat adipose tissue amino acid metabolism in vivo as assessed by microdialysis and arteriovenous techniques,” American Journal of Physiology, vol. 273, no. 3, pp. E613–E622, 1997. View at: Google Scholar
  37. C. F. Wolf and F. S. Keck, “Thyroxine and reverse T3 5deiodination in the cells of human adipose tissue,” Thyroidology, vol. 3, no. 2, pp. 47–50, 1991. View at: Google Scholar
  38. J. Ukropec, R. P. Anunciado, Y. Ravussin, M. W. Hulver, and L. P. Kozak, “UCP1-independent thermogenesis in white adipose tissue of cold-acclimated Ucp1-/- mice,” Journal of Biological Chemistry, vol. 281, no. 42, pp. 31894–31908, 2006. View at: Publisher Site | Google Scholar

Copyright © 2010 Fiona E. Mitchell et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

More related articles

 PDF Download Citation Citation
 Download other formatsMore
 Order printed copiesOrder

Related articles

We are committed to sharing findings related to COVID-19 as quickly as possible. We will be providing unlimited waivers of publication charges for accepted research articles as well as case reports and case series related to COVID-19. Review articles are excluded from this waiver policy. Sign up here as a reviewer to help fast-track new submissions.