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Tryptophan and iodothyronine transport interactions in HepG2 human hepatoma cells

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Abstract

This study identifies interactions between transport of the aromatic amino acid l-tryptophan (Trp) and thyroid hormones (TH) in HepG2 human hepatoma cells. The major portion of Trp uptake in HepG2 cells occurs via the NEM-sensitive amino acid transport System L2 (consistent with hepatic LAT3 expression), with a smaller aromatic-AA selective System T (MCT10) component. LAT3 and MCT10 mRNA were both detected in HepG2 cells. Uptake of TH does not involve System L2, but a significant portion of T3 uptake is mediated by System T, alongside a taurocholate-sensitive organic anion transporter. T4 uptake into HepG2 cells appears to be mediated principally by organic anion/monocarboxylate transporters, with smaller contributions by System T and receptor-mediated endocytosis. TH–Trp transport interactions in liver cells centre on System T which, due to a perivenous localisation alongside deiodinase 1, may impact on hepatic T3 generation and release.

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References

  • Abe T et al (1998) Molecular characterization and tissue distribution of a new organic anion transporter subtype (oatp3) that transports thyroid hormones and taurocholate and comparison with oatp2. J Biol Chem 273:22395–22401

    Article  CAS  PubMed  Google Scholar 

  • Abe T et al (1999) Identification of a novel gene family encoding human liver-specific organic anion transporter LST-1. J Biol Chem 274:17159–17163

    Article  CAS  PubMed  Google Scholar 

  • Abe T, Suzuki T, Unno M, Tokui T, Ito S (2002) Thyroid hormone transporters: recent advances. Trends Endocrinol Metab 13:215–220

    Article  CAS  PubMed  Google Scholar 

  • Babu E et al (2003) Identification of a novel system L amino acid transporter structurally distinct from heterodimeric amino acid transporters. J Biol Chem 278:43838–43845

    Article  CAS  PubMed  Google Scholar 

  • Blondeau JP, Osty J, Francon J (1988) Characterization of the thyroid hormone transport system of isolated hepatocytes. J Biol Chem 263:2685–2692

    CAS  PubMed  Google Scholar 

  • Bodoy S, Martin L, Zorzano A, Palacin M, Estevez R, Bertran J (2005) Identification of LAT4, a novel amino acid transporter with system L activity. J Biol Chem 280:12002–12011

    Article  CAS  PubMed  Google Scholar 

  • Friesema EC et al (1999) Identification of thyroid hormone transporters. Biochem Biophys Res Commun 254:497–501

    Article  CAS  PubMed  Google Scholar 

  • Friesema EC, Ganguly S, Abdalla A, Manning Fox JE, Halestrap AP, Visser TJ (2003) Identification of monocarboxylate transporter 8 as a specific thyroid hormone transporter. J Biol Chem 278:40128–40135

    Article  CAS  PubMed  Google Scholar 

  • Friesema EC, Jansen J, Milici C, Visser TJ (2005) Thyroid hormone transporters. Vitam Horm 70:137–167

    Article  CAS  PubMed  Google Scholar 

  • Friesema EC, Kuiper GG, Jansen J, Visser TJ, Kester MH (2006) Thyroid hormone transport by the human monocarboxylate transporter 8 and its rate-limiting role in intracellular metabolism. Mol Endocrinol 20:2761–2772

    Article  CAS  PubMed  Google Scholar 

  • Friesema ECH, Jansen J, Jachtenberg J-w, Visser WE, Kester MHA, Visser TJ (2008) Effective cellular uptake and efflux of thyroid hormone by human monocarboxylate transporter 10. Mol Endocrinol 22:1357–1369

    Article  CAS  PubMed  Google Scholar 

  • Gereben B, Zavacki AM, Ribich S, Kim BW, Huang SA, Simonides WS, Zeold A, Bianco AC (2008) Cellular and molecular basis of deiodinase-regulated thyroid hormone signaling. Endocr Rev 29:898–938

    Article  CAS  PubMed  Google Scholar 

  • Goenner S, Boutron A, Soni T, Lemonnier A, Moatti N (1992) Amino acid transport systems in the human hepatoma cell line Hep G2. Biochem Biophys Res Commun 189:472–479

    Article  CAS  PubMed  Google Scholar 

  • Hennemann G, Docter R, Friesema EC, de Jong M, Krenning EP, Visser TJ (2001) Plasma membrane transport of thyroid hormones and its role in thyroid hormone metabolism and bioavailability. Endocr Rev 22:451–476

    Article  CAS  PubMed  Google Scholar 

  • Horiuchi R, Cheng SY, Willingham M, Pastan I (1982) Inhibition of the nuclear entry of 3,3′,5′-triiodo-l-thyronine by monodansylcadaverine in GH3 cells. J Biol Chem 257:3139–3144

    CAS  PubMed  Google Scholar 

  • Inui KI, Masuda S, Saito H (2000) Cellular and molecular aspects of drug transport in the kidney. Kidney Int 58:944–958

    Article  CAS  PubMed  Google Scholar 

  • Kaper T, Looger LL, Takanaga H, Platten M, Steinman L, Frommer WB (2007) Nanosensor detection of an immunoregulatory tryptophan influx/kynurenine efflux cycle. PLoS Biol 5:e257

    Article  PubMed  Google Scholar 

  • Kemp HF, Taylor PM (1997) Interactions between thyroid hormone and tryptophan transport in rat liver are modulated by thyroid status. Am J Physiol 272:E809–E816

    CAS  PubMed  Google Scholar 

  • Kim DK, Kanai Y, Chairoungdua A, Matsuo H, Cha SH, Endou H (2001) Expression cloning of a Na+-independent aromatic amino acid transporter with structural similarity to H+/monocarboxylate transporters. J Biol Chem 276:17221–17228

    Article  CAS  PubMed  Google Scholar 

  • Pizzagalli F, Hagenbuch B, Stieger B, Klenk U, Folkers G, Meier PJ (2002) Identification of a novel human organic anion transporting polypeptide as a high affinity thyroxine transporter. Mol Endocrinol 16:2283–2296

    Article  CAS  PubMed  Google Scholar 

  • Ramadan T, Camargo SM, Summa V, Hunziker P, Chesnov S, Pos KM, Verrey F (2006) Basolateral aromatic amino acid transporter TAT1 (Slc16a10) functions as an efflux pathway. J Cell Physiol 206:771–779

    Article  CAS  PubMed  Google Scholar 

  • Riley WW Jr, Eales JG (1994) Characterization of 3,5,3′-triiodo-l-thyronine transport into hepatocytes isolated from juvenile rainbow trout (Oncorhynchus mykiss), and comparison with l-thyroxine transport. Gen Comp Endocrinol 95:301–309

    Article  CAS  PubMed  Google Scholar 

  • Ritchie JW, Taylor PM (2001) Role of the System L permease LAT1 in amino acid and iodothyronine transport in placenta. Biochem J 356:719–725

    Article  CAS  PubMed  Google Scholar 

  • Ritchie JW, Shi YB, Hayashi Y, Baird FE, Muchekehu RW, Christie GR, Taylor PM (2003) A role for thyroid hormone transporters in transcriptional regulation by thyroid hormone receptors. Mol Endocrinol 17:653–661

    Article  CAS  PubMed  Google Scholar 

  • Rose DP (1972) Aspects of tryptophan metabolism in health and disease: a review. J Clin Pathol 25:17–25

    Article  CAS  PubMed  Google Scholar 

  • Salter M, Knowles RG, Pogson CI (1986) Transport of the aromatic amino acids into isolated rat liver cells. Properties of uptake by two distinct systems. Biochem J 233:499–506

    CAS  PubMed  Google Scholar 

  • Smith PK et al (1985) Measurement of protein using bicinchoninic acid. Anal Biochem 150:76–85

    Article  CAS  PubMed  Google Scholar 

  • Taylor PM, Ritchie JW (2007) Tissue uptake of thyroid hormone by amino acid transporters. Best Pract Res Clin Endocrinol Metab 21:237–251

    Article  CAS  PubMed  Google Scholar 

  • Taylor PM, Baird FE, Christie GR, Hayashi Y, Ritchie JWA (2003) Membrane transporters as modulators of protein metabolism. Nova Acta Leopoldina 87(329):321–331

    CAS  Google Scholar 

  • van der Deure WM, Hansen PS, Peeters RP, Kyvik KO, Friesema EC, Hegedus L, Visser TJ (2008a) Thyroid hormone transport and metabolism by organic anion transporter 1C1 and consequences of genetic variation. Endocrinology 149:5307–5314

    Article  PubMed  Google Scholar 

  • van der Deure WM et al (2008b) Organic anion transporter 1B1: an important factor in hepatic thyroid hormone and estrogen transport and metabolism. Endocrinology 149:4695–4701

    Article  PubMed  Google Scholar 

  • van Stralen PG, van der Hoek HJ, Docter R, de Jong M, Krenning EP, Everts ME, Hennemann G (1996) Uptake and metabolism of 3,5,3′-triiodothyronine and 3,3′,5′-triiodothyronine by human liver-derived cells: HepG2 cells as a model for thyroid hormone handling by human liver. J Clin Endocrinol Metab 81:244–248

    Article  PubMed  Google Scholar 

  • Verrey F, Closs EI, Wagner CA, Palacin M, Endou H, Kanai Y (2004) CATs and HATs: the SLC7 family of amino acid transporters. Pflugers Arch 447:532–542

    Article  CAS  PubMed  Google Scholar 

  • Yen PM (2001) Physiological and molecular basis of thyroid hormone action. Physiol Rev 81:1097–1142

    CAS  PubMed  Google Scholar 

  • Zandieh Doulabi B, Platvoet-ter Schiphorst M, van Beeren HC, Labruyere WT, Lamers WH, Fliers E, Bakker O, Wiersinga WM (2002) TR{beta}1 protein is preferentially expressed in the pericentral zone of rat liver and exhibits marked diurnal variation. Endocrinology 143:979–984

    Article  PubMed  Google Scholar 

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Acknowledgments

We are grateful to the UK Biotechnology and Biological Sciences Research Council and Tenovus (UK) for financial support, Fiona Mitchell and Lisa Roy for technical assistance and Dr Calum Sutherland for the gift of HepG2 cell cDNA.

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  1. Division of Molecular Physiology, College of Life Sciences, James Black Centre, University of Dundee, Dundee, DD1 5EH, UK

    James W. A. Ritchie & Peter Maving Taylor

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  1. James W. A. Ritchie
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  2. Peter Maving Taylor
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Correspondence to Peter Maving Taylor.

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Ritchie, J.W.A., Taylor, P.M. Tryptophan and iodothyronine transport interactions in HepG2 human hepatoma cells. Amino Acids 38, 1361–1367 (2010). https://doi.org/10.1007/s00726-009-0344-6

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  • DOI: https://doi.org/10.1007/s00726-009-0344-6

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