Effect of hypothyroidism on pathways for iodothyronine and tryptophan uptake into rat adipocytes

James W. A. Ritchie, Charmian J. F. Collingwood, and Peter M. Taylor

School of Life Sciences, University of Dundee, Dundee DD1 5EH, Scotland, United Kingdom


    ABSTRACT
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ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
REFERENCES

Adipocytes are an important target tissue for thyroid hormone action, but little is known of the mechanisms of thyroid hormone entry into the cells. The present results show a strong interaction between transport of iodothyronines [L-thyroxine (T4), L-triiodothyronine (T3), reverse T3 (rT3)], aromatic amino acids, and the System L amino acid transport inhibitor 2-amino[2,2,1]heptane-2-carboxylic acid (BCH) in white adipocytes. System L appears to be a major pathway of iodothyronine and large neutral amino acid entry into these cells in the euthyroid state. We also demonstrate expression of the CD98hc peptide subunit of the System L transporter in adipocyte cell membranes. Experimental hypothyroidism (28-day propylthiouracil treatment) has no significant effect on System L-like transport of the amino acid tryptophan in adipocytes. In contrast, uptake of T3 and especially T4 is substantially reduced in adipocytes from hypothyroid rats, partly due to reduction of the BCH-sensitive transport component. Transport of iodothyronines and amino acids in adipocytes therefore becomes decoupled in the hypothyroid state, as occurs similarly in liver cells. This may be due to downregulation or dissociation of iodothyronine receptors from the System L transporter complex. Regulation of iodothyronine turnover in fat cells by this type of mechanism could contribute significantly to modulation of T4-T3/rT3 metabolism in the hypothyroid state.

adipose tissue; amino acid; thyroid hormone; membrane transport


    INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
REFERENCES

THE THYROID HORMONES L-thyroxine (T4) and L-triiodothyronine (T3) exert their major physiological effects by regulating gene expression in target cells. The hormones must therefore cross the plasma membrane to reach their intracellular destination within the nucleus (12, 13). White adipose tissue is an important target tissue for thyroid hormone action, where effects include modulation of fatty acid synthesis via regulation of expression of lipogenic enzymes (3) as well as modulation of hormone sensitivity via regulation of expression of receptor number (29). There is a surprising lack of knowledge of the mechanisms of thyroid hormone entry into adipocytes, although there is growing evidence that iodothyronines enter other cell types using a variety of mechanisms (1, 4, 7, 15, 32) including transporters for large zwitterionic amino acids (4, 25, 28).

The major transporter of large zwitterionic amino acids in mammalian cells is termed System L (16, 30) and is composed of a heterodimer of two peptides, CD98hc and an isoform of the LAT permeases (5). We have recently established that this transporter also accepts iodothyronines as substrates (25). Major System L substrates also include the branched-chain amino acids (BCAA) and aromatic amino acids (16, 24). Rat adipose tissue is a site of significant BCAA degradation and utilization for fatty acid synthesis (8, 27). BCAA (notably leucine) also appear to be involved in modulation of the p70S6 kinase signaling pathway in adipocytes (6). Nevertheless, the mechanisms effecting and modulating transport of BCAA and aromatic amino acids in adipose tissue are as poorly characterized as those of iodothyronines. In the present study, we have therefore investigated routes of entry of iodothyronines into fat cells, focusing on pathways that interact with transport of large zwitterionic amino acids, as well as on effects of hypothyroidism on the uptake processes.


    EXPERIMENTAL PROCEDURES
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ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
REFERENCES

Materials and animals. All chemicals were obtained from Sigma (Poole, UK) unless stated otherwise. Radioactive tracers were obtained from NEN Research Products (Stevenage, UK). Male Wistar rats of 250 g initial weight were purchased from Bantin and Kingman (Hull, UK) and maintained on a standard laboratory diet. Rats were made hypothyroid by addition of 0.05% propylthiouracil (PTU) to drinking water for 28 days (15, 21). Development of a hypothyroid state was confirmed from measurement of markedly elevated plasma thyroid-stimulating hormone (TSH) concentration (35.5 ± 6.0 mU/l; n = 8 rats) relative to control rats (3.3 ± 0.7 mU TSH/l; n = 8).

Isolation of adipocytes. Hypothyroid and control (euthyroid) rats were killed by cervical dislocation, and their epididymal fat pads were removed immediately. Adipocytes were harvested at 37°C from the fat pads by use of collagenase (type II) in Krebs-Ringer phosphate buffer, pH 7.4, containing 20 mg/ml bovine serum albumin (26).

Transport studies. Tryptophan (Trp) and iodothyronine uptakes were measured at 37°C in 450 µl of the cell suspension, to which were added 50 µl of reaction buffer to start measurement. For Trp studies, the reaction buffer consisted of Krebs-Ringer containing L-[3H]Trp (0.05 mM final concentration unless stated otherwise) and [14C]inulin as an extracellular marker with a 3H-to-14C ratio of 10:1. For iodothyronine studies, the reaction buffer consisted of Krebs-Ringer containing [125I]T4 (4 nM) or [125I]T3 (4.5 nM unless stated otherwise), and extracellular ([14C]inulin) space was measured in separate experiments performed in parallel. The cell suspension was continuously agitated during the incubation period. Uptake was terminated after a timed period by transferring 300 µl of the reaction mixture to a 400-µl Eppendorf microtest tube (BDH, Poole, UK) containing 100 µl of diisononylphthalate (Riedel-de Haen, Aberdeen, UK) and by centrifuging for 20 s in a microcentrifuge. The adipocytes remained on top of the oil while the reaction buffer passed through the oil layer to lie below it. The test tube was then cut in two just above and below the cell layer, and the section of tube containing the cells was transferred to a scintillation vial for liquid spectrometric assay of radioactivity. Tracer uptake into adipocytes was corrected for adhering extracellular radioactivity (estimated as [14C]inulin space). Adipocyte cell number was estimated by counting live (trypan blue-excluding) cells under a microscope with the use of a hemocytometer.

In certain experiments, adipocytes were preincubated with either the endocytosis inhibitor monodansylcadaverine [0.1 mM; (14)] or the organic anion hippurate (0.1-10 mM) for 30 min before uptake assay.

Membrane isolation and Western blotting. Adipocyte membranes were prepared by subcellular fractionation as described elsewhere (11). Membrane proteins were resolved by SDS-PAGE and electroblotted onto nitrocellulose membranes. CD98hc (4F2hc) protein (5, 30) was detected immunologically using enhanced chemiluminescence (Amersham) with anti-rat CD98hc (goat) obtained from Santa Cruz Biotechnology (Santa Cruz, CA). The primary antibody was used at 1:250 and horseradish peroxidase-labeled secondary antibody (donkey anti-goat; Scottish Antibody Production Unit, Carluke, UK) was used for visualization.

Data analysis. The data are expressed as means ± SE for n adipocyte preparations, where each experimental measurement in an individual preparation was performed in triplicate. Statistical significance was assessed using Student's t-test; differences were considered significant where P < 0.05.


    RESULTS
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ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
REFERENCES

Iodothyronine uptake into euthyroid rat adipocytes. In preliminary experiments, we established that uptake of [125I]T4 and [125I]T3 was linear with time for >= 15 min (Fig. 1A). In experiments described below, the initial rate of tracer iodothyronine uptake was measured over 10 min. Extrapolation of uptake to zero time for the two tracers revealed instantaneous binding components equivalent to 11 and 37% of total uptake over this time period for T4 and T3, respectively (Fig. 1A). Total uptake of T4 and T3 (at 4 and 4.5 nM, respectively) into adipocytes included substantial saturable components (Fig. 2) that were sensitive to inhibition by iodothyronines including reverse T3 (rT3; Fig. 2) and also by the amino acids Trp, phenylalanine, and 2-amino[2,2,1]heptane-2-carboxylic acid (BCH; Fig. 2 and data not shown). The iodothyronine concentration used in inhibitor experiments (10 µM) is close to the water solubility limit of these compounds, and concentrations of amino acid inhibitors used were found to produce maximal effects in preliminary experiments. The synthetic amino acid analog BCH is used throughout this study as a specific inhibitor of System L-mediated solute transport (16, 24).


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Fig. 1.   Time courses of uptake of thyroxine (T4; A), triiodothyronine, and tryptophan (T3; A Trp; B) into euthyroid rat adipocytes. A: uptake of [125I]-labeled T4 (4 nM) or [125I]-labeled T3 (4.5 nM) was measured over the denoted time periods at 37°C in isolated rat adipocytes. Results are presented as total iodothyronine uptake, expressed as means ± SE for 3 (T4) or 6 preparations (T3). B: uptake of [3H]Trp (1 µM) was measured over the denoted time periods at 37°C in isolated rat adipocytes. Results are presented as total Trp uptake, expressed as means ± SE for 4 preparations.



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Fig. 2.   Effect of amino acids and iodothyronines on uptake of T4 and T3 into isolated euthyroid rat adipocytes. Uptake of [125I]T4 (4 nM) or [125I]T3 (4.5 nM) was measured in the presence and absence of potential inhibitors for 10 min at 37°C in isolated rat adipocytes. Results are presented as means ± SE for 4-8 preparations. All inhibitions were significantly different from zero (P < 0.05). Inhibitor concentrations used were: Trp, 10 mM; 2-amino[2,2,1]heptane-2-carboxylic acid (BCH), 1 mM; T4, reverse T3, and T3 10 µM.

System L transport in euthyroid rat adipocytes. In view of the inhibitory effect of BCH on tracer T4 and T3 uptake, we subsequently focused on System L transport as a major pathway for iodothyronine transport in adipocytes. Western blotting confirmed the presence of the System L transporter heavy chain (CD98hc) in adipocyte membranes (Fig. 3). The CD98hc glycoprotein is seen as a broad band centered at 86 kDa under reducing conditions and as a 130-kDa protein complex [presumably with transporter light chains such as LAT1 (5, 30)] under nonreducing PAGE conditions. This is consistent with previous observations of the behavior of CD98hc protein in other cell types (5, 30). We next investigated interactions between iodothyronines and amino acid substrates of System L. We used Trp as our amino acid of study because it is a System L substrate and has well-characterized interactions with iodothyronine transport in several cell types (4, 15, 28). Uptake of L-[3H]Trp tracer into adipocytes reached an equilibrium value within 1 min (Fig. 1B), and the initial rate of tracer tryptophan uptake was measured over 10 s. Extrapolation of Trp uptake to zero time revealed an instantaneous binding component equivalent to 52% of total uptake over this time period (Fig. 1B). Trp uptake into adipocytes was unaffected by replacement of Na+ in the transport buffer with choline ions and therefore appears to be Na+ independent (data not shown). Uptake of 1 µM [3H]Trp into adipocytes included a substantial saturable component (Table 1) that was sensitive to inhibition by excess of large zwitterionic amino acids (unlabeled L- and D-Trp, phenylalanine, BCH; Table 1 and data not shown), as well as by iodothyronines, including T4, rT3, and, to a lesser extent, T3 (Table 1). Inhibition of Trp uptake by T4 and BCH was not additive (therefore it may occur possibly by a common System L-mediated pathway; see Table 1). Saturable Trp uptake at Trp concentration ([Trp]) between 1 µM and 5 mM (Fig. 4) appeared to consist of a single transport component with estimated values for the Michaelis-Menten constant of 0.23 mM and maximal velocity of 40 pmol Trp · 100,000 cells-1 · 10 s-1.


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Fig. 3.   Expression of CD98hc in rat adipocyte membranes. Western blot of euthyroid adipocyte membrane proteins (40 µg) probed with anti-rat CD98hc. Samples prepared under reducing and nonreducing conditions [with and without beta -mercaptoethanol (B-MeOH), respectively] are shown in adjacent lanes. Rat kidney microsomes are shown as a positive control where indicated.


                              
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Table 1.   Effect of putative inhibitors on tryptophan uptake in euthyroid rat adipocytes



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Fig. 4.   Saturable Trp uptake into euthyroid rat adipocytes. Hanes plot relating [3H]Trp uptake in euthyroid rat adipocytes (corrected for nonsaturable component) against external Trp concentration. Inset: raw transport data (n = 3 measurements at each [Trp]). The saturable transport component has an estimated Michaelis-Menten constant of 0.23 mM and maximum velocity of 40 pmol Trp · 100,000 cells-1 · 10 s-1.

The instantaneous (zero-time) binding components of T4, T3, and Trp tracers were not displaced by excess unlabeled BCH (1 mM); thus a BCH-sensitive transport component represents the major part (61, 67, and 52%, respectively) of the "time-dependent" tracer influx (i.e., total uptake - instantaneous uptake) for all three tracers. The balance of total tracer uptake is likely to include components from specific high-affinity binding sites, partitioning of tracer into the adipocyte membrane, passive diffusion, and endocytosis. Some involvement of the latter process in total Trp uptake is indicated by the fact that it is partly inhibited by the endocytosis inhibitor monodansylcadaverine (Table 1), although monodansylcadaverine had no statistically significant effect on uptake of iodothyronines by adipocytes (data not shown). The organic anion hippurate had no significant effect on Trp or T3 uptake, although it had a slight (35 ± 4%) stimulatory effect on T4 uptake.

Effects of hypothyroidism and desipramine on iodothyronine uptake into rat adipocytes. Experimental hypothyroidism resulted in substantial decreases in both saturable and total uptake of T4 and (to a lesser extent) T3 by adipocytes (Fig. 5). The decrease occurred largely in an uptake component sensitive to inhibition by BCH, indicative of reduced iodothyronine transport through System L (Table 2). In contrast, BCH-sensitive Trp transport in adipocytes (an index of overall System L transport activity) was not significantly affected by altered thyroid status from the euthyroid value (Table 2). Overall, these data are consistent with an uncoupling of iodothyronine uptake from System L-mediated amino acid transport in hypothyroid adipocytes. A substantial component of uptake of both iodothyronines and Trp in euthyroid adipocytes was also sensitive to inhibition by the tricyclic antidepressant desipramine (Table 3). Desipramine is reported to interact with iodothyronine uptake into rat brain in a manner dependent on thyroid status (9) and also to inhibit Trp transport by System L [CD98-IU12 heterodimers (25)] expressed in Xenopus oocytes (unpublished observations of J. W. A. Ritchie, G. R. Christie and P. M. Taylor). Desipramine-sensitive transport of T4, but not of Trp, is significantly reduced in adipocytes from hypothyroid rats (Table 3), an effect similar to that seen with BCH-sensitive transport of these substances (Table 2).


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Fig. 5.   Uptake of T4 (A) and T3 (B) in euthyroid and hypothyroid rat adipocytes. Uptake of [125I]T4 (4 nM) or [125I]T3 (4.5 nM) tracers was measured in the presence and absence of unlabeled iodothyronine competitors (T4 and T3, both at 10 µM) for 10 min at 37°C in isolated rat adipocytes. Results are expressed as means ± SE for 4-6 preparations. Tracer uptake in the absence of inhibitor was significantly (P < 0.05) lower in hypothyroid than in euthyroid state for both T4 and T3. Inhibition of tracer uptake by unlabeled iodothyronines was statistically significant (P < 0.05), except where denoted not significant (NS).


                              
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Table 2.   Effect of experimental hypothyroidism on iodothyronine and tryptophan uptake by System L in rat adipocytes


                              
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Table 3.   Desipramine-sensitive uptake of iodothyronines and tryptophan in euthyroid and hypothyroid rat adipocytes


    DISCUSSION
TOP
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
REFERENCES

The present studies have revealed strong interactions between transport processes for iodothyronines and large zwitterionic amino acids in white adipocytes from the rat. These interactions (plus common inhibition of uptake by BCH) indicate that the Na+-independent System L transporter contributes substantially to iodothyronine and large neutral amino acid transport in adipocytes, at least in the euthyroid state. This view is supported by our previous discovery that iodothyronines (including T4, T3 and rT3) are substrates for the System L transporter overexpressed in oocytes (25) and is strengthened by the observations that rT3 is an effective inhibitor of the uptake of Trp, T4, and T3 into rat adipocytes. We have further observed that both L- and D-Trp inhibit tracer L-Trp and L-T3 transport in adipocytes, and this lack of stereoselectivity for L-isomers as substrates is also consistent with known functional characteristics of System L (16, 30). Functional measurements of System L transport activity in adipocytes are supported by immunological detection of the CD98hc subunit of the heteromeric System L transporter in adipocyte cell membranes. Self and reciprocal inhibition between uptake of T4 and T3 into adipocytes is not significantly greater than inhibition by BCH. System L may therefore be the major carrier for iodothyronines in the adipocyte plasma membrane and thus for delivery of thyroid hormones from the plasma to the cytosol, where, ultimately, they reach the cell nucleus. Certain organic anion transporters are also known to accept iodothyronines as substrates (1, 7). The organic anion hippurate does not inhibit either iodothyronine or Trp transport here (indeed, it has a minor stimulatory effect on T4 uptake), but we cannot exclude the possibility that some iodothyronines cross adipocyte membranes by hippurate-insensitive organic anion transporters. A small but significant proportion of Trp uptake may be by an endocytotic pathway inhibitable by monodansylcadaverine (14), but we find no evidence that this pathway is an important route for iodothyronine entry into adipocytes.

The antidepressant desipramine inhibits both iodothyronine and Trp uptake in euthyroid adipocytes and is also reported to affect uptake and turnover of thyroid hormones and Trp in other rat tissues (2, 9). We now have evidence that desipramine inhibits Trp uptake by System L overexpressed in Xenopus oocytes and here show that desipramine- and BCH-sensitive T4 uptakes are reduced to a similar extent in hypothyroid rat adipocytes. These observations are consistent with our suggestion that System L mediates the greater part of saturable iodothyronine transport in adipocytes. Nevertheless, the diverse effects of desipramine also include potent inhibition of transporters for biogenic amines (e.g., norepinephrine, serotonin). Therefore, given that there is a high activity of norepinephrine transport in white adipocytes (23), we cannot exclude the possibility of additional interactions between amine and amino acid receptor-transporter mechanisms in the process of iodothyronine uptake by adipocytes.

T4 and rT3 are more effective inhibitors than T3 of Trp uptake under our experimental conditions. We did not find them to be preferred over T3 as substrates of System L overexpressed in oocytes (25), but it is conceivable that they are preferentially targeted for transport by specific receptors in the adipocyte membrane. There is evidence that iodothyronine transport in other cell types (e.g., hepatocytes, erythrocytes) may be facilitated by co-operative interactions between transporters and iodothyronine receptors on the plasma membrane (15, 28, 32). High-affinity receptors for both T4 and T3 have been identified associated with the plasma membrane of adipocytes (17, 22), and these may be involved in iodothyronine uptake.

The System L transporter is likely to be the major saturable route of entry for large neutral amino acid transport into adipocytes. In contrast, small neutral amino acids are reported to be taken up into adipocytes by the Na+-dependent amino acid transport systems A (10) and ASC (19). Experimental hypothyroidism has no significant effect on BCH-sensitive uptake of Trp in adipocytes, indicating that there is no overall change in System L transporter activity in this condition. In contrast, there are substantial reductions in saturable uptake of T3 (by 48%) and in particular T4 (by 79%) in adipocytes from hypothyroid rats, due at least partly to reduction in activity of a BCH-sensitive transport component. These results are consistent with an uncoupling between transport of iodothyronines and amino acids in the hypothyroid state, as we have observed previously in liver cells (15). Thus BCH-sensitive amino acid transport is retained, but that of thyroid hormones is reduced, arguing against a generalized effect of hypothyroidism, such as change in cell size (20), on adipose tissue transport properties. We have hypothesized elsewhere that thyroid-dependent interactions between transport of iodothyronines and amino acids include downregulation or decoupling of iodothyronine receptors from an amino acid transporter complex in the hypothyroid state (15). The System L transporter heavy chain CD98hc is known to exhibit functional interactions with other membrane proteins (e.g., integrins) in addition to its covalent associations with a transporter light chain such as LAT1 (5); therefore, a direct interaction between CD98hc and iodothyronine receptors is conceivable.

White adipose tissue has the capacity to deiodinate T4 and (especially) rT3 by action of 5'-deiodinase (31). Given that white adipose tissue represents ~18% of body mass on average, regulation of iodothyronine turnover in fat cells through this pathway could contribute significantly to modulation of whole body T4-rT3 metabolism. It is therefore relevant to note that the system L transporter operates an exchange mode (16, 30) that may enable amino acid-T4 or T4-T3/rT3 exchanges (15, 32) across the adipocyte plasma membrane. Further work is required to reveal whether this mechanism also contributes to the metabolically important processes of iodothyronine turnover in brown adipose tissue (29). Rat adipose tissue in vivo releases tyrosine (18), a System L substrate that may exchange at least partly for uptake of iodothyronines. In the hypothyroid state, downregulation of transport at the cell membrane would tend to reduce T4 and rT3 catabolism and help conserve hormone and iodine availability to other tissues. Adipose tissue sensitivity to hormonal activation is generally repressed in hypothyroidism, but the relative retention of T3 uptake capacity should enable this more active hormone to maintain some metabolic effect in adipocytes. System L transport activity for amino acids in adipocytes is not downregulated by hypothyroidism, and indeed, there is evidence that BCAA metabolism in fat tissue is increased in hypothyroidism (8), driven by upregulation of BCAA catabolic enzymes in adipocytes.


    ACKNOWLEDGEMENTS

We are indebted to Ian Hannings (Ninewells Hospital and Medical School, Dundee) for measurement of plasma TSH concentrations, Dr. Gary Litherland for preparation of rat adipocyte membranes, and Tatiana Panova for technical assistance.


    FOOTNOTES

This work was supported by the UK Biotechnology and Biological Sciences Research Council and the University of Dundee.

Address for reprint requests and other correspondence: Dr. Peter M. Taylor, School of Life Sciences, MSI/WTB Complex, Univ. of Dundee, Dundee DD1 5EH, Scotland, UK (E-mail: p.m.taylor{at}dundee.ac.uk).

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 7 March 2000; accepted in final form 20 October 2000.


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ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
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Am J Physiol Endocrinol Metab 280(2):E254-E259
0193-1849/01 $5.00 Copyright © 2001 the American Physiological Society




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