Cellular Uptake of Thyroid Hormones
Last Updated: July 21, 2010
Authors
 Theo J. Visser, Ph.D.
Department of Internal Medicine III Erasmus University Medical School Molewater Plein 50
Dr. 3015 GE, Rotterdam THE NETHERLANDS Tel: 011-31-10-463-5463 Fax: 011-31-10-4635430
During the last three decades it has become clear that thyroid hormones (THs) are transported into cells
by specific carrier-mediated uptake mechanisms. Before that time, it was thought that crossing the
plasma membrane of tissue cells is a matter of simple diffusion as THs are lipophilic compounds which
can easily pass the lipid bilayer of the plasma membrane. There is now a vast literature showing that
this is apparently not the case. In fact, diffusion probably plays a minor role, if any, in TH transport
across the plasma membrane. Several TH transporters have recently been identified. Mutations in one
of these (MCT8) are the cause of a syndrome combining severe psychomotor retardation and abnormal
serum TH levels.
Clinical summary
About 80% of circulating T3 is produced outside the thyroid gland by peripheral conversion of T4, and
only 20% is directly secreted by the thyroid gland (1). T3 is considered to be the major bioactive TH,
whereas T4 is mainly a prohormone that becomes activated upon its conversion to T3 (1). Most TH
actions are initiated by binding of T3 to its nuclear receptors in target cells (2). Therefore, the
biological activity of TH is determined largely by the intracellular T3 concentration, which depends on
a) the circulating concentration of T3 and its precursor T4; b) the activities of deiodinases that catalyze
the production (D1, D2) or degradation (D3) of T3; and c) the activities of transporters which mediate
the cellular uptake or efflux of T3 and T4 (Fig. 1). It should be noted that TH bioactivity may be
regulated in an autocrine fashion as shown in Fig. 1, or in a paracrine fashion, where T3 production and
action take place in the same cell or in separate cells, respectively.
In this chapter literature will be reviewed published mostly before 2000, dealing with the biochemical
characterization of TH uptake into different cell types. The results of these studies were used to explain
clinical observations of changes in TH transport and metabolism as observed during fasting and nonthyroidal illness (NTI). For a detailed review of this literature, the reader is referred to Ref. (3). In
addition, studies will be reviewed published mostly after 2000, dealing with the molecular
characterization of different TH transporters.
The older studies have indicated that THs cross the plasma membrane by specific processes that may
be energy and/or Na dependent (3). In vitro studies using different cell types have shown that inhibition
of T3 transport into the cell leads to a proportionate decrease in nuclear T3 binding. Furthermore,
cellular TH uptake determines subsequent metabolism (e.g. T3 production from T4) (3). Studies in the
intact perfused rat liver, as well as in humans, have shown that hepatic TH uptake is diminished when
cellular ATP is transiently decreased by fructose administration (4). The fasting-induced decrease in TH
uptake in liver and other tissues may also be mediated by a reduction in cellular ATP (5). In humans,
fasting is associated with relatively normal serum TSH and FT4 but low T3 levels, reflecting a reduced
peripheral T4 to T3 conversion (6). This “low T3 syndrome” may be caused by decreased outer ring
deiodinase activities in the tissues, e.g. D1 in the liver, as well as decreased uptake of T4 in T3
producing tissues such as the liver.
The lowering of T3 production in NTI is more complicated than that resulting from caloric deprivation
alone. In both situations, tissue TH uptake may be diminished by a reduction of cellular ATP as well as
by competition of serum non-esterified fatty acids, which at high concentrations inhibit T4 uptake in
hepatocytes (3). However, in NTI hepatic T4 uptake may also be inhibited by other competitors whose
serum concentrations are increased. These include bilirubin in patients with liver disease and toxins
such as indoxyl sulfate in patients with renal disease (3). Furthermore, drugs may also have an effect on
TH tissue uptake.
The low serum T3 induced by caloric deprivation and NTI is considered by many to be an adaptation
mechanism, since energy and protein (i.e. organ function) are conserved (7). Because the patients are
not clearly hypothyroid, the term “euthyroid sick syndrome” is used synonymously. Others believe that
the patients are hypothyroid and advocate replacement therapy with TH. If possibly treatment is
beneficial will depend on the type, duration and severity of the disease, and if this is associated with a
true decrease in thyroid function with low T4 production rates.
Recently, three relatively specific TH transporters have been identified. OATP1C1 is a member of the
organic anion transporting polypeptide family, which shows preference for T4 above T3, and is
expressed almost exclusively in brain, in particular in capillaries (8). OATP1C1 is probably important
for T4 transport across the blood-brain barrier. MCT8 and MCT10 are members of the
monocarboxylate transporter family. While MCT10 is also known to transport aromatic amino acids, no
other substrates have been identified for MCT8 than iodothyronines (9-11). Both MCT8 and MCT10
are expressed in various tissues (12). Mutations in the MCT8 transporter have been identified in male
patients with the Allan-Herndon-Dudley syndrome, combining severe X-linked psychomotor
retardation and elevated serum T3 levels (13-15)
Cellular transport of thyroid hormone
Most of the early studies, showing carrier-mediated uptake, were performed with rat liver cells. In the
late 1970s, Rao et al. (16) and Krenning et al. (17) independently showed that T3 is taken up by rat
liver cells by a carrier-mediated process that is energy and Na+ dependent. In subsequent years, carriermediated T3 transport was identified in many cell types, including hepatoma cells, glial cells, neurons,
pituitary cells, choriocarcinoma cells, myocytes, red and white blood cells, thymocytes, and fibroblasts
(3). Transport of T4 has been studied much less extensively than T3 transport. Energy dependence of
TH transport was noticed in different but not all cell types. In hepatocytes, T4 transport is more
sensitive to a decrease in cellular ATP than T3 transport (3). Evidence has been presented that TH
uptake in different cell types may be mediated by Na-independent, L-type or T-type amino acid
transporters (18-22). The former transports large, neutral amino acids, while the latter is specific for
aromatic amino acids.
TH uptake in hepatocytes appears to involve multiple high-affinity, low-capacity and low-affinity, highcapacity processes, with Km values in the nanomolar and micromolar ranges, respectively (3). As
serum free T4 and T3 concentrations are in the picomolar range, liver TH uptake will not be saturated
at even supraphysiological TH levels. Inhibition of TH transport by structurally related compounds is
also seen. The best known are amiodarone, aromatic amino acids, benzodiazepine, and iodinecontaining X-ray contrast agents (3). Furthermore, TH uptake in the liver, but not in the pituitary, is
also inhibited by substances like fatty acids, indoxyl sulfate and bilirubin, that circulate in increased
amounts in patients with non-thyroidal illness. T4 and T3 transport into liver cells may be mediated at
least in part by different transporters (23). In contrast, in the rat pituitary T4 and T3 are reported to
share the same transport site (24).
Several findings indicate that TH transport over the plasma membrane is rate-limiting for intracellular
metabolism. Thus, inhibitors of uptake of T4, T3 and rT3 in rat hepatocytes induce a decrease in the
deiodination of these iodothyronines without having an effect on the deiodination process itself (25).
Furthermore, binding of T3 to its nuclear receptor is dependent on the rate of T3 transport across the
plasma membrane (3, 26).
Cellular TH availability is not only dependent on its rate of uptake but also on the rate of TH efflux. As
for TH uptake, TH efflux does not seem to take place by diffusion but also requires transporters. Many
transporters involved in TH transport are capable of bidirectional transport and facilitate the exchange
of intra- and extracellular substrates (see below). In addition, evidence has been presented for specific
cellular efflux of TH by multidrug-resistance related proteins in different cell types (27-29).
Uptake of thyroid hormone in the perfused liver
After fasting of rats for 2 days, cellular T3 uptake in the isolated perfused liver is decreased by 40%
(30). Transport normalizes within 0.5 h when insulin, cortisol and/or glucose are added to the perfusion
medium, probably because of the restoration of cellular energy stores (30). The importance of cellular
energy charge for TH uptake is supported by findings that fructose induces an acute decrease in cellular
ATP with a parallel decrease in T4 uptake in the perfused rat liver (4). After treatment of rats with
amiodarone, T4 uptake in the isolated perfused liver is inhibited whereas T3 uptake is not affected (31).
In agreement with findings in hepatocyte cultures, this suggests that T4 and T3 are taken up by liver
cells via different transporters. Hepatic TH transport may also be regulated by thyroid state as T3
uptake is decreased in livers from hyperthyroid rats, although it is not altered in livers from
hypothyroid animals (32).
Tissue uptake of thyroid hormones in humans
Tissue TH uptake has been studied in humans by analysis of the clearance of injected radioactive
iodothyronines from plasma into a rapidly equilibrating tissue pool (largely liver) and a slowly
equilibrating tissue pool. In one such study it was demonstrated that fructose administration results in a
marked transient decrease in hepatic T4 uptake (4). This was accompanied by an increase in serum
lactate and uric acid levels, indirectly reflecting a decrease in liver ATP (4). Obese but otherwise
healthy volunteers subjected to a calorie-restricted diet show a decrease in T4 and T3 uptake into both
rapidly and slowly equilibrating tissues (5).
Different studies have reported on human subjects with abnormally low serum T3/T4 ratios, apparently
reflecting a decreased peripheral T4 to T3 conversion in the absence of known causes of the low T3
syndrome such as fasting, illness and certain drugs. In one such patient, a 60 years old T4-substituted
woman, TH kinetic studies were performed as described above (33). The results indicated decreased
transport of T4 into the rapid tissue pool (liver), but a normal T4 transport into other tissues. Tissue T3
transport was normal. Total peripheral T3 production was decreased but relative to the available hepatic
T4 pool, it was unaltered, indicating normal enzymatic T4 to T3 conversion. It was concluded that the
inhibition of T4 transport into the liver leads to low normal serum T3 and an elevated serum T4,
resulting in a decreased T3/T4 ratio. Analysis of genomic DNA of another patient with a similar serum
TH phenotype revealed no structural abnormalities of the coding and 5′-flanking region of the type 1
iodothyronine deiodinase gene (34, 35)
Transporters
Organic anion transporters
Organic anion transporting polypeptides (OATPs) represent a large family of homologous proteins,
many of which have been shown to transport different iodothyronines and their sulfate conjugates
(Table 1) (36-38). The genes coding for these transporters are now referred as the SLCO family. The
OATPs accept a wide range of substrates, not only anionic but also neutral and sometimes even cationic
compounds. Some members are expressed in a single tissue, whereas others have a wider tissue
distribution. Interestingly, the SLCO1A2, 1B1, 1B3 and 1C1 genes are clustered together with a related
pseudogene on human chromosome 12p12 (38). The encoded OATPs have all been shown to transport
iodothyronines (39). Of these, OATP1B1 and 1B3 are expressed specifically in the liver, OATP1C1 is
expressed only in brain and testis, and OATP1A2 is expressed in brain, liver and kidney. In terms of TH
transport, OATP1C1 is the most intriguing as it shows a high specificity and affinity towards T4 and
rT3. In brain, it is localized preferentially in capillaries, suggesting that OATP1C1 is particularly
important for transport of T4 across the blood-brain barrier (8, 40, 41).
OATPs transport their substrates in a Na-independent manner. The solute carrier family 22 (SLC22)
also contains many organic anion transporters (OATs) and organic anion transporters (OCTs), but
information about the possible transport of TH by any of these transporters has not been published. We
have demonstrated that the Na-taurocholate cotransporting polypeptide (NTCP, SLC10A1) facilitates
uptake of the different iodothyronines as well as their sulfates (42, 43). The SLC10 family contains 7
members of which NTCP is expressed exclusively in liver (44, 45). SLC10A2 is another bile acid
transporter expressed in the intestine and kidney. SLC10A6 transports different organic anions but
substrates for the other SLC10 transporters have not yet been identified. NTCP is the only SLC10
family member capable of transporting TH (43).
Amino acid transporters
Iodothyronines are a particular class of amino acids built from two tyrosine residues. Therefore, it is no
surprise that amino acid transporters, in particular the L and T-type amino acid transporters, are
involved in TH uptake into several tissues (18-22). L-type transporters mediate uptake of large neutral,
branched-chain and aromatic amino acids, whereas T-type transporters are specific for the aromatic
amino acids Phe, Tyr and Trp.
Recently, two L-type transporters (LAT1 and LAT2) have been identified among the members of the
heterodimeric amino acid transporter family. These transporters consist of a heavy chain and a light
chain, linked through a disulfide bond (46). There are 2 possible heavy chains (4F2hc and rBAT)
belonging to the SLC3 gene family, and in humans there are 13 possible light chains belonging to the
SLC7 gene family. The 4F2 or CD98 cell surface antigen is expressed in many tissues, especially on
activated lymphocytes and tumor cells. 4F2hc is a glycosylated protein with a single transmembrane
domain, whereas the light chains are not glycosylated and have 12 transmembrane domains (46). The
LAT1 and LAT2 light chains form a functional transporter with the 4F2hc heavy chain.
Significant Na-independent transport of iodothyronines has been observed in Xenopus oocytes
expressing heterodimeric transporters consisting of human 4F2hc and either human LAT1 or mouse
LAT2 (Table 1) (47). The rate of iodothyronine uptake by the 4F2hc/LAT1 transporter decreased in the
order 3,3′-T2 > T3 ~ rT3 > T4. Apparent Km values were found to be in the micromolar range, being
lowest for T3 (1.5 µM) (47).
Ritchie et al. have reported on the stimulation of T3 transport in oocytes injected with mRNA for
4F2hc and for the IU12 Xenopus LAT1 homolog (48). They have also shown that overexpression of the
heterodimeric L type transporter in cells results in increased intracellular T3 availability and, thus,
augmented T3 action (49). Furthermore, they demonstrated T3 uptake via the 4F2hc/LAT1 transporter
into the human BeWo placental choriocarcinoma cell line, suggesting that this transporter plays an
important role in the transplacental transfer of maternal TH to the fetus (50).
A T-type amino acid transporter (TAT1) has been cloned from rats and humans, and shown to transport
Phe, Tyr and Trp (51, 52). This protein is a member of the monocarboxylate transporter family, and is
also called MCT10 (SLC16A10). The MCT family consists of 14 members, and earned its name
because MCT1-4 have been characterized as monocarboxylate transporters but the substrates
transported by most other MCTs have not been identified. The degree of homology is particularly high
between MCT1-4 and between MCT8 and 10. In contrast to the initial failure to demonstrate TH
transport by MCT10, we have demonstrated that both MCT8 and MCT10 are highly effective
iodothyronine transporters (Table 1) (9-11).
MCT8 and MCT10
MCT8 and MCT10 have identical gene structures; both consist of 6 exons and 5 introns, with a
particularly long first intron (~100 kb). The MCT10 gene is located on human chromosome 16q21-q22
and codes for a protein of 515 amino acids. The MCT8 gene is located on human chromosome Xq13.2
and has 2 possible translation start sites, coding for proteins of 613 or 539 amino acids (Fig. 2). The
significance of the N-terminal extension of long versus short human MCT8 (indicated in yellow in Fig.
2) remains to be investigated. Most species, including mice and rats, only express the short MCT8
protein as they lack the first translation start site. Functional studies of human MCT8 have been carried
out so far by expression of the short protein variant.
Both MCT8 and MCT10 proteins have 12 putative transmembrane domains, with both N- and Cterminal ends located on the inside of the plasma membrane. The common amino acids in MCT8 and
MCT10 are indicated in green in Fig. 2, showing a high degree of homology in particular in the
transmembrane domains. Unique to the MCT8 structure is the presence of PEST domains in the Nterminal intracellular part of the protein, rich in Pro (P), Glu (E), Ser (S) and Thr (T) residues. The
function of these domains is unknown. MCT8 is expressed in many tissues, including human liver,
kidney, heart, brain, placenta, adrenal gland, skeletal muscle, and thyroid. MCT10 also shows a wide
tissue distribution, with particularly high expression in human skeletal muscle, intestine, kidney and
pancreas (12).
After the cloning of MCT8 in 1994 (53), no reports on the biological function or the transported
substrates have been published until Friesema et al. identified rat MCT8 as a specific TH transporter
(10). Expression of MCT8 in Xenopus oocytes induced a ~10-fold increase in iodothyronine uptake,
much greater than that induced by any other transporter, including rat NTCP, rat OATP1A1 and human
LAT1 (10). Although rat MCT8 does not discriminate between T4, T3, rT3 and 3,3′-T2, it does not
transport iodothyronine sulfates, the amino acids Phe, Tyr, Trp and Leu, or the monocarboxylates
lactate and pyruvate. Apparent Km values amount to 2-5 µM for the different iodothyronines in the
absence of protein in the medium. T4 and T3 transport are largely Na-independent (10).
Subsequent studies in mammalian cells transfected with human MCT8 or MCT10 cDNA have
demonstrated that both transporters effectively facilitate transmembrane transport of TH (9, 11). Cotransfection of the high-affinity cytoplasmic TH-binding protein mu-crystallin strongly augments the
cellular accumulation of iodothyronines compared with cells transfected with MCT8 or MCT10 alone.
These and other findings suggest that MCT8 and MCT10 facilitate both cellular uptake and efflux of
T4 and T3. MCT10 appears to transport T3 better than MCT8 whereas the opposite is true for T4.
Transfection of MCT8 or MCT10 into cells that express D1, D2 or D3 results in a marked increase in
the intracellular metabolism of different iodothyronine substrates (9, 11).
Clinical relevance of MCT8
Worldwide, at least 50 families have been reported where males are affected by severe psychomotor
retardation associated with a particular combination of abnormal serum TH levels. A large family with
this X-linked mental retardation (XLMR) syndrome was first reported in 1944 by Allan, Herndon and
Dudley (54, 55). Since then, this disorder is usually referred to as the Allan-Herndon-Dudley syndrome
(AHDS). Only 60 years later it was realized that patients with AHDS also have abnormal TH levels
(14, 56, 57).
Usually, patients with AHDS are born at term following an uncomplicated pregnancy with a normal
birthweight, body length and head circumference. During the first 6 months a general hypotonia is
noticed. During development the truncal hypotonia remains, whereas the distal hypotonia progresses
into spasticity. The truncal hypotonia results in poor head control. Growth is relatively normal, but final
body length is reduced and body weight is usually extremely low with obvious signs of muscle
wasting. There is also progressive microcephaly. In the first 2 years of life, brain MRI shows a delayed
myelination but this normalizes in subsequent years. Based on observations of delayed myelination, the
above clinical features have also been referred to as Pelizaeus-Merzbacher-like disorder (PMLD) (58).
Although in some families the clinical phenotype is somewhat milder, AHDS patients are usually
incapable of sitting, standing or walking independently, and do not develop any speech. They are
severly mentally retarded with IQ values <40. Feeding is a problem in AHDS patients as they have
difficulties swallowing; aspiration is a frequent cause of pneumonia. For a detailed description of the
clinical features of patients with AHDS, the reader is referred to recent literature (58-61).
AHDS patients have a characteristic combination of abnormal serum TH levels (60). Both T4 and FT4
levels are low-normal to clearly reduced, whereas serum T3 and FT3 are markedly elevated. Serum rT3
is always low. Consequently, the serum T3/T4 and T3/rT3 ratios are strongly elevated. Serum TSH is
usually within the normal range, but the mean serum TSH level in AHDS patients is about twice that in
healthy controls. Serum SHBG levels are markedly elevated, and several studies have reported on
elevated serum lactate levels in young patients (62, 63).
In 2004, it was demonstrated by the group of Refetoff and by our group that AHDS represents a TH
resistance syndrome caused by a defect in TH uptake in target cells due to mutations in MCT8 . Since
then, MCT8 mutations have been identified in over 50 families with AHDS; published mutations are
listed in Table 2. These mutations include 1) rather large deletions affecting one or more exons, 2)
smaller deletions or insertions which result in a shift in the reading frame, leading to scrambled and/or
truncated proteins; 3) nonsense mutations resulting in truncated proteins; 4) three-nucleotide and thus
one-amino acid deletions or insertions, 5) missense mutations asociated with single amino acid
substitutions, and 6) a splice site mutation, resulting in a deletion of 94 amino acids and 3
transmembrane domains.
The larger deletions, frame shift mutations and nonsense mutations are oviously deleterious for MCT8
function. The functional consequences of single amino acid substitutions, deletions or insertions have
been investigated in cells transfected with wild-type or mutated MCT8. Most mutations were found to
result in an amost complete loss of TH transport by MCT8. However, the extent to which these
mutations affect MCT8 function depends on the type of cell used for transfection for reasons which
need to be fully explored (64-67).
Animal studies
Studies in humans and animals have indicated that MCT8 is expressed in a variety of tissues, including
brain. The distribution of MCT8 expression in mouse brain has been studied in detail by Heuer et al
(68). These studies have demonstrated that MCT8 is predominantly expressed in neurons in different
brain areas, including hippocampus, cerebral cortex, striatum, hypothalamus and cerebellum. In
addition, MCT8 is importantly expressed in capillary endothelial cells, the choroid plexus, and
tanycytes which line the third ventricle (68, 69). MCT8 expression in neurons coincides with
expression of D3. D2 is largely expressed in adjacent astrocytes. The T4 transporter OATP1C1 is
expressed in capillaries and in the choroid plexus (68, 69).
Figure 3 shows a scheme of the regulation of T3 supply to neuronal target cells, based on studies by
Heuer et al (68) and Bernal et al (70). The steps involved in this process include 1) transport of T4 by
OATP1C1 through the blood-brain-barrier, 2) uptake of T4 in astrocytes by an unidentified transporter,
3) conversion of T4 to T3 by D2 in astrocytes, 4) release of T3 from the astrocytes by another
unidentified transporter, 5) uptake of T3 in neurons by MCT8. These neurons may also express D3 for
termination of T3 activity. This schema is an oversimplification as it ignores the importance of TH
transport across the blood-brain barrier by MCT8, and across the blood-CSF barrier by both MCT8 and
OATP1C1, as well as the importance of other target cells for TH in the brain such as oligodendrocytes.
MCT8 (KO) mice have been studied by Trajkovic et al (71), Dumitrescu et al (72), and Wirth et al
(73). In contrast to the severe neurological phenotype in male patients with MCT8 mutations, neither
hemizygous MCT8 KO male mice nor homozygous MCT8 KO female mice show an obvious
phenotype. However, they show the same deviations in serum thyroid parameters as patients with
MCT8 mutations, i.e. a large decrease in T4, a large increase in serum T3, and slightly elevated TSH
levels. In addition, MCT8 KO mice show the following features: 1) normal brain T4 uptake but
impaired brain T3 uptake, 2) decreased brain T4 and T3 contents, 3) increased D2 and decreased D3
activities in brain, 4) normal liver T4 and T3 uptake, 5) increased kidney T4 and T3 uptake, 6)
increased kidney T4 and T3 contents, and 7) increased D1 activity in both liver and kidney (74).
The paradoxical increase in renal T4 and T3 uptake in MCT8 KO mice is unexplained, but the increase
in renal T4 content in combination with the increased D1 expression may account for an enhanced
renal T4 to T3 conversion, and thus contribute to the decrease in serum T4 and increase in serum T3
(74). In addition, there is evidence suggesting that thyroidal hormone secretion is affected by MCT8
inactivation, leading to preferential T3 secretion (75). Since MCT8 is expressed in the hypothalamus,
inactivation of MCT8 is associated with an impaired feedback of TH at the hypothalamic level,
contributing to the slightly increased serum TSH level (71). The lack of an obvious phenotype in
MCT8 KO mice remains to be explained.
Pathogenesis
TH plays an essential role in brain development. This requires optimal spatio-temporal regulation of T3
supply to brain target cells, in particular neurons. MCT8 is supposed to be crucial for T3 transport into
central neurons. Inactivation of MCT8 deprives neurons of active T3, resulting in an impaired
development of the central nervous system and thus in severe psychomotor retardation. It is also
possibe that MCT8 is more important for T3 uptake in certain subsets of neurons than for others. This
may result in a dysbalance of T3 supply to different neuronal populations and thus in a defect in the
coordinated development of neuronal networks in the brain.
Depending on the importance of MCT8 for T3 transport across the blood-brain barrier and choroid
plexus, mutation of MCT8 may also result in an overall lower brain T3 uptake as is seen in MCT8 KO
mice. Moreover, it is not excluded that the abnormal circulating T4 and T3 levels themselves are
detrimental for brain development. Which pathogenic mechanism is responsible for the psychomotor
retardation may have important consequences for the management of patients with MCT8 mutations.
In addition to the TH dysregulation in the brain, the effects of MCT8 mutations on the thyroid state of
peripheral tissues should also be considered. Usually, the heart appears to function normally in MCT8
patients despite exposure to highly elevated serum T3 levels. This suggest a partially impaired cardiac
T3 upake in case of a MCT8 mutation, implying the involvement of additional TH transporters in the
heart. MCT8 patients show extensive muscle wasting and increased serum SHBG levels, which likely
reflect a hyperthyroid state of the skeletal muscles and liver, respectively (hepatic SHBG production is
increased by TH). This would indicate that MCT8 inactivation does not impair muscle and liver T3
uptake, suggesting a more important role of other transporters. Finally, findings in MCT8 KO mice
suggest that the kidneys are also in a hyperthyroid state in MCT8 patients, but there is no direct
evidence for this assumption.
Conclusions and perspectives
Much progress has been made in recent years with the identification of TH transporters and their role in
the tissue-specific regulation of TH bioactivity in health and disease. However, it is likely that
important TH transporters still remain to be discovered. For instance, none of the TH transporters
characterized recently at the molecular level have the properties of transporters involved in TH uptake
in liver cells, such as nanomolar affinities, ATP and Na dependence, as determined in previous studies.
Further, the physiological relevance of OATP1C1 and MCT10 need to be demonstrated. Although it
has been demonstrated that mutations in MCT8 cause severe psychomotor retardation, the pathogenic
mechanism has not been established. For this it is essential to know exactly where MCT8 is expressed
in the human brain and other tissues. While a beginning has been made with the treatment of AHDS
patients with T3 analogs which do not require MCT8 for cell uptake, much further work is needed to
develop an optimal therapy for these patients.
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