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Transthyretin and the human placenta
Placenta 34 (2013) 513e517
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Current opinion
Transthyretin and the human placenta K.A. Landers a, *, R.H. Mortimer b, c, K. Richard a, b a
Conjoint Endocrine Laboratory, Pathology Queensland, Royal Brisbane and Women’s Hospital, Herston, 4006 Brisbane, Australia Discipline of Medicine, The University of Queensland, Herston, 4006 Brisbane, Australia c Discipline of Obstetrics and Gynaecology, The University of Queensland, Herston, 4006 Brisbane, Australia b
a r t i c l e i n f o
a b s t r a c t
Article history: Accepted 19 April 2013
Since its discovery, transthyretin (TTR) has been regarded as an important hepatically derived protein carrier of thyroid hormones and retinol in blood. However, in more recent years it has been shown that TTR has other important functions. TTR is abundant in cerebrospinal fluid, where it may be involved in transport of thyroid hormones into the brain. TTR derived amyloid is associated with diseases such as senile systemic amyloidosis, familial amyloid polyneuropathy and familial amyloid cardiomyopathy. Recently, synthesis, secretion and uptake of TTR by human placenta have been reported. TTR appears to play an important role in the delivery of maternal thyroid hormone to the developing fetus. This review explores the various proposed roles of TTR and more recent findings on TTR synthesis and expression in the placenta. Crown Copyright Ó 2013 Published by Elsevier Ltd. All rights reserved.
Keywords: Transthyretin Placenta Thyroid hormone
1. Introduction It has become increasingly apparent that transthyretin (TTR) has roles that extend beyond those of a transporter of thyroid hormone and retinol in the serum. In this review we outline the many roles of TTR in different tissues before focussing on the more recently discovered placental synthesis, secretion and uptake of TTR. We highlight the potential importance of TTR during early fetal development and the additional research required in this area.
2. Transthyretin Transthyretin (TTR) formerly known as pre-albumin, was first discovered in 1942 both in human cerebrospinal fluid [1] and blood [2]. The term pre-albumin was used because TTR migrated ahead of albumin during electrophoresis. The name transthyretin was introduced in 1981 to reflect the protein’s roles in the transport (trans-) of thyroid hormone (-thy-) and retinol (-retin) [3]. TTR is derived from a gene duplication event of the Transthyretin-like protein gene. Transthyretin-like protein hydrolyses 5-hydroxyisourate in the purine catalytic pathway and is present in most organisms. TTR seems to have developed early in vertebrate evolution and is highly conserved amongst many animal
* Corresponding author. Conjoint Endocrine Laboratory, Royal Brisbane and Women’s Hospital, 300 Herston Rd, Herston, 4029 Brisbane, Queensland, Australia. Tel.: þ61 7 3362 0495; fax: þ61 7 3636 8842. E-mail address: [email protected] (K.A. Landers).
species including human, mouse, sheep, rat, fish, rabbit, lizard and chicken [4]. 2.1. Structure TTR is a 55 kDa homotetrameric protein comprising four identical 14 kDa subunits [5,6]. Approximately 45% of the amino acids in the TTR monomer are arranged into eight b-strands, names A through H, connected by loops, which result in a classic B barrel conformation [5]. Only 5% of amino acid residues in the monomer are in a short a-helix [7]. Dimers of TTR are composed of a pair of twisted eight-stranded b-sheets. The association of two dimers gives a tetrameric structure. The strength of the interactions identified between the monomers (resulting in a dimer) and between the dimers (forming a tetramer) suggests that the dimer rather than the monomer or tetramer is the most stable unit of the TTR structure [8]. The TTR tetramer is stable between pH 3.5e12 and has the ability to assemble subunits of different TTR molecules to form hybrid tetramers. 2.2. Function The main recognised function of TTR is the transport of thyroid hormone and retinol throughout the body. Thyroid hormone is extremely hydrophobic and is carried in blood bound to three hepatically secreted thyroid hormone binding proteins, thyroxine binding globulin (TBG), TTR and albumin. TBG has the highest affinity for thyroxine (T4) (affinity constant, Ka ¼ 1.0 1010M1), followed by TTR (7.0 107 M1) and albumin (7.0 105 M1). TBG
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carries 65% of circulating T4 in the blood stream, whilst TTR transports 15% of T4 [9]. In contrast, TTR is the main carrier of T4 in the cerebrospinal fluid (CSF) [10]. TTR in tetrameric form has two thyroid hormone binding sites, but only one binding site is occupied under physiological conditions [11] due to negative co-operativity [12]. Tetrameric TTR has four binding sites for retinol binding protein (RBP) however, due to steric hindrance, a maximum of two molecules can bind per tetramer [13]. Under physiological conditions the TTR tetramer binds one RBP molecule only. RBP is synthesised in endoplasmic reticulum of the liver, where it binds retinol. The RBP-retinol complex binds TTR before it is secreted into plasma. The majority of retinol is delivered to cells via the TTR-RBP-retinol complex. Retinoids (retinol and its derivatives) control many biological functions such as vision, reproduction, development, growth and immunity [14]. In pregnancy retinoids are crucial for the mother’s health, maintenance of placenta and the developing embryo [15]. A recent functional study of TTR has demonstrated that it has protease activity. A small percentage of TTR circulates in blood bound to Apolipoprotein (Apo) A-1 and acts as a protease [16]. In vitro TTR was able to proteolytically cleave the carboxyl-terminal domain of Apo-A1. Only a small fraction of TTR is proteolytically active. Proteolytic TTR has also been shown to promote neurite outgrowth [17] suggesting a role in the nervous system and to prevent amyloid beta fibril formation, which accumulates in Alzheimer’s disease [18]. Other ligands of TTR include plant flavonoids [19], lysosomeassociated membrane protein (LAMP-1) [20] and a number of synthetic ligands including hydroxylated polychlorinated biphenyls [21], brominated flame-retardants [22] and non-steroidal anti-inflammatory drugs [23]. 2.3. Diseases associated with dysfunctional TTR Amyloid fibrils of TTR are the main constituent of senile systemic amyloidosis (SSA), familial amyloid polyneuropathy (FAP), familial amyloid cardiomyopathy (FAC) and central nervous system-associated amyloidosis (CNSA). SSA affects 25% of people over the age of 80 years and results from deposition of mainly wildtype TTR predominantly in cardiac tissue [24]. Mutated TTR variants lead to familial forms of amyloidosis such as FAP, FAC and CNSA. Familial amyloidosis is inherited in an autosomal dominant manner and can arise from one of over 100 mutated TTR variants that destabilise the TTR tetramer [25]. FAP is associated with progressive sensorimotor polyneuropathy, whilst FAC occurs later in life [26,27]. CNSA is also late-onset and due to amyloid found in the leptomeninges of the brain [28] and can be associated with dementia and ataxia [29]. Decreased levels of TTR have been observed in CSF of Alzheimer’s patients, where TTR is thought to prevent formation of the characteristic amyloid beta plaques [18]. CSF TTR levels are decreased in Alzheimer’s patients [30] and negatively correlate with degree of dementia [31]. Dysregulated placental TTR has been found in cases of intrauterine growth restriction and severe early onset preeclampsia [32]. While a causative role of TTR in preeclampsia has been postulated [33] there is little evidence for this. It is well known that insufficient levels of thyroid hormone during development leads to irreversible brain damage [34], even slight alterations in thyroid hormone levels during the first 12 weeks of gestation can result in reduced IQ [35]. Reduced levels of thyroid hormone in adults results in a myriad of symptoms including depression [36]. Interestingly, patients with depression have reduced levels of TTR [37,38] and TTR knockout mice have been shown to develop depressive-like behaviour [39].
Animal studies have also suggested that TTR has a role in behaviour, cognition and nerve regeneration [40]. 2.4. Synthesis and secretion TTR synthesis has been identified in the liver [41], choroid plexus [10], yolk sac [42], placenta [43], pancreas [44] and intestine [45] of humans. In other species, heart, skeletal muscle, stomach, spleen, the meninges [46], retinal pigment epithelia [47] and ciliary pigment epithelia [48] synthesise TTR. Liver and choroid plexus are the most abundant and well-described sites of TTR synthesis in humans and it is now clear that TTR is a product of human placenta. TTR synthesised by hepatocytes is secreted basally into the blood stream (0.2e0.25 mg/ml) [49]. This circulating pool of TTR contributes to the distribution of hydrophobic thyroid hormones in the blood stream [50]. In choroid plexus TTR is synthesised by the epithelial cells [10] and secreted apically into the CSF [51]. Choroid plexus has the highest concentration of TTR mRNA in the body and TTR accounts for 12% of all proteins synthesised. The secretion of TTR into ventricles is dependant on synthesis of new protein [52]. In CSF, 80% of T4 is bound to TTR whereas only 15% of T4 is bound to TTR in serum [10]. In rodents, it is proposed that newly synthesised TTR binds to T4 either in CP or after secretion into the CSF, the TTRT4 complex is then transported to the brain parenchyma [53,54]. It is yet to be determined whether this is true in humans. High levels of TTR have been observed in fetal serum as early as 13 weeks gestation at a time when fetal liver TTR mRNA expression is very low [41]. More recently it was discovered that TTR expression localised to placental trophoblasts [43]. Furthermore, TTR mRNA and protein are expressed as early as 6 weeks gestation in placental tissue and demonstrate significant time dependent linear increases in early pregnancy (6e13 weeks). From 13 to 17 weeks gestation both TTR mRNA and protein levels plateau and are similar to levels at term [55]. TTR secreted from polarised trophoblasts is mostly apical into the maternal circulation, with some secreted from the basal membrane [56]. This was confirmed in experiments using dually perfused placental lobules where newly synthesised TTR was secreted into both the maternal and fetal circuits [57]. One hundred times more TTR was secreted into the maternal compared with the fetal circulation. 2.5. Internalisation Studies of TTR internalisation in hepatomas and primary hepatocytes suggested that hepatic TTR uptake is mediated by a receptor of the low-density lipoprotein (LDL) receptor family [58]. TTR internalisation in renal cells involved a receptor identified as megalin (LRP2), an endocytic multi-ligand receptor of the LDL receptor family [59]. Furthermore, in sensory neurons of mice TTR internalisation is clathrin dependent, and megalin mediated [60] Internalisation of TTR by trophoblasts is a recent discovery. In the presence of T4, TTR uptake is increased [56] a phenomenon that Divino and Schussler as well as Sousa and Saraiva observed in hepatoma cells [61,62]. T4 binding stabilised the TTR tetramer and increased TTR internalisation [56] suggesting that the TTR-T4 tetramer is endocytosed. Interestingly, tetramer formation induced by the TTR stabilisers diflunisal and iodo-diflunisal did not increase internalisation [56]. Hence, it was proposed that placental TTR binds maternal T4 and is internalised by trophoblast cells. The ‘free hormone hypothesis’ was first proposed by Recant and Riggs in 1952 and states that the biological activity of a hormone in vivo can only be predicted by its unbound form because only free hormones are taken up by cells [63,64]. Clearly a transthyretin-mediated cell uptake of T4 challenges this idea.
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Using mathematical modelling and experiments with perfused placental lobules, a model was proposed for the synthesis, secretion and uptake of TTR in the placenta [57]. The best-fit model suggested that TTR was secreted into the maternal circulation where it could be taken back up into the placenta and subsequently secreted into the fetal circuit. Internalisation of TTR from the maternal circuit of the perfused placental lobule was low, however T4 was absent from the experiment and this may have reduced internalisation. High local concentrations of TTR at the maternaleplacental interface may bind maternal T4 for shuttling to the fetal capillaries. Interestingly, Alexa-labelled TTR (in the presence of T4) could be demonstrated in fetal capillaries in early (14e15 weeks gestation) and late (38e40 weeks gestation) placental explants [57]. 2.6. Regulation Costa and Grayson discovered that TTR gene expression in hepatocytes is regulated by two 50 UTR regions, a proximal promoter region and a distal enhancer region [65]. These two regions contain binding sites for HNF, CCAAT/enhancer binding protein (C/EBP) and AP-1/cjun that contribute to transcriptional regulation in hepatocytes. Within the choroid plexus, the HNFs are absent and it is thought TTR is regulated by transcription factors that are closely related to the HNFs [66]. This demonstrates that there is tissue specific regulation. In placenta the transcriptional binding proteins, HNF-3 (or FOXa2), C/ EBP and AP-1 are expressed throughout gestation and are involved in activating transcription of a number of genes important for fetal development [67,68]. Patel et al. (2012) reported an increase in TTR promoter activity in choriocarcinoma cells when cells were cultured at 1% oxygen (hypoxic conditions) [69]. Interestingly, C/EBP and AP-1 are also up-regulated in hypoxic conditions and interact with hypoxia-inducible factor-1a (HIF-1a) [70]. Furthermore, TTR mRNA and protein expression increased in choriocarcinoma cells and primary trophoblast cells cultured at 1% oxygen compared with cells cultured at 8% or 21% oxygen [71]. This may be physiologically important considering during the first trimester of pregnancy the placenta is relatively hypoxic with oxygen levels of 1e3% (15e18 mm Hg) at the time of implantation [72,73]. Following placental development and invasion into the maternal decidua (8e10 weeks) oxygen levels rise to 3e5% (18 mm Hg) and by the end of the first trimester (12e13 weeks) oxygen concentrations are at 7e10% (60 mm Hg) and remain here until birth [72]. However, this was not reflected in the ontogenic data collected on TTR mRNA and protein measured in placenta tissue, which increased with gestation (i.e. as oxygenation increased) [69]. This highlights the complexity of the placenta and the many factors regulating gene transcription and translation within this tissue. 3. Conclusion Clearly TTR has many different roles that go beyond that of a serum carrier of thyroid hormone and retinol. Since our discovery of TTR synthesis in the placenta we have reported that it is secreted predominantly into the maternal circulation where it can also be taken back up by trophoblasts in the presence of T4. During pregnancy the fetus starts to produce thyroid hormone from approximately 12 weeks gestation. Prior to 12 weeks gestation fetal thyroid hormone supply is from the mother, which can continue throughout pregnancy if required. The mechanisms underlying this maternalefetal transfer of thyroid hormone are poorly understood. It is known that the placenta has high levels of deiodinase type 3 activity which inactivates T4 to its inactive form rT3. The presence of TTR in the placenta as early as 6 weeks gestation may play an important role in binding maternal T4, preventing deiodination and delivering it to fetal capillaries.
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TTR appears to be internalised by trophoblasts in its tetrameric form in the presence of T4, suggesting TTR-T4 are internalised as a complex. Further research is required to establish the nature of this internalisation and which membrane transporters may be involved. Internalisation of T4 bound to a carrier protein (TTR) would challenge the ‘free hormone hypothesis’ [63,64] and suggests that there are other pathways involved in cellular uptake of T4. One of the main functions of TTR in the liver and choroid plexus is to ensure even distribution of thyroid hormone either in the blood or brain, respectively. It will be important to investigate if TTR plays a similar role in the placenta or maternal compartments of the placenta. Regulation of TTR in liver and choroid plexus is very different. Liver TTR expression is down-regulated during an acute phase response [74] whilst choroid plexus TTR is not affected under the same conditions [66] preventing detrimental disruptions in the thyroid hormone economy of the brain. Identifying how TTR is regulated in the placenta throughout gestation is of interest as current evidence suggests it plays a role in the handling of T4 during this time. Finally, TTR has been highly conserved throughout evolution, mutations in the gene are heterozygous and there have been no reports of a human with a gene deletion of TTR. All of these points suggest that TTR plays a pivotal role in the human body. Further research on the roles of TTR is essential in order for us to fully understand this remarkable protein. References [1] Kabat EA, Moore DH, Landow H. An electrophoretic study of the protein components in cerebrospinal fluid and their relationship to the serum proteins. Journal of Clinical Investigation 1942;21(5):571e7. [2] Seibert FB, Nelson JW. Electrophoretic study of the blood protein response in tuberculosis. Journal of Biological Chemistry 1942;143(1):29e38. [3] Nomenclature Committee of IUB (NC-IUB) IUB-IUPAC Joint Commission on Biochemical Nomenclature (JCBN). Newsletter 1981. Journal of Biological Chemistry 1981;256(1):12e4. [4] Power DM, Elias NP, Richardson SJ, Mendes J, Soares CM, Santos CR. Evolution of the thyroid hormone-binding protein, transthyretin. General and Comparative Endocrinology 2000;119(3):241e55. [5] Blake CC, Geisow MJ, Oatley SJ, Rerat B, Rerat C. Structure of prealbumin: secondary, tertiary and quaternary interactions determined by Fourier refinement at 1.8 A. Journal of Molecular Biology 1978;121(3):339e56. [6] Blake CC, Swan ID, Rerat C, Berthou J, Laurent A, Rerat B. An x-ray study of the subunit structure of prealbumin. Journal of Molecular Biology 1971;61(1):217e24. [7] Blake CC, Geisow MJ, Swan ID, Rerat C, Rerat B. Structure of human plasma prealbumin at 2e5 A resolution. A preliminary report on the polypeptide chain conformation, quaternary structure and thyroxine binding. Journal of Molecular Biology 1974;88(1):1e12. [8] Robbins J, Cheng SY, Gershengorn MC, Glinoer D, Cahnmann HJ, Edelnoch H. Thyroxine transport proteins of plasma. Molecular properties and biosynthesis. Recent Progress in Hormone Research 1978;34:477e519. [9] Schreiber G. The evolutionary and integrative roles of transthyretin in thyroid hormone homeostasis. The Journal of Endocrinology 2002;175(1):61e73. [10] Herbert J, Wilcox JN, Pham KT, Fremeau Jr RT, Zeviani M, Dwork A, et al. Transthyretin: a choroid plexus-specific transport protein in human brain. The 1986 S. Weir Mitchell award. Neurology 1986;36(7):900e11. [11] Wojtczak A, Cody V, Luft JR, Pangborn W. Structures of human transthyretin complexed with thyroxine at 2.0 A resolution and 30 ,50 -dinitro-N-acetyl-Lthyronine at 2.2 A resolution. Acta Crystallographica Section D, Biological Crystallography 1996;52(Pt 4):758e65. [12] Ferguson RN, Edelhoch H, Saroff HA, Robbins J, Cahnmann HJ. Negative cooperativity in the binding of thyroxine to human serum prealbumin. Preparation of tritium-labeled 8-anilino-1-naphthalenesulfonic acid. Biochemistry 1975;14(2):282e9. [13] Monaco HL, Rizzi M, Coda A. Structure of a complex of two plasma proteins: transthyretin and retinol-binding protein. Science 1995;268(5213): 1039e41. [14] Blomhoff R, Blomhoff HK. Overview of retinoid metabolism and function. Journal of Neurobiology 2006;66(7):606e30. [15] Clagett-Dame M, DeLuca HF. The role of vitamin A in mammalian reproduction and embryonic development. Annual Review of Nutrition 2002;22:347e81. [16] Liz MA, Faro CJ, Saraiva MJ, Sousa MM. Transthyretin, a new cryptic protease. The Journal of Biological Chemistry 2004;279(20):21431e8. [17] Liz MA, Fleming CE, Nunes AF, Almeida MR, Mar FM, Choe Y, et al. Substrate specificity of transthyretin: identification of natural substrates in the nervous system. The Biochemical Journal 2009;419(2):467e74.
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Current opinion
Transthyretin and the human placenta K.A. Landers a, *, R.H. Mortimer b, c, K. Richard a, b a
Conjoint Endocrine Laboratory, Pathology Queensland, Royal Brisbane and Women’s Hospital, Herston, 4006 Brisbane, Australia Discipline of Medicine, The University of Queensland, Herston, 4006 Brisbane, Australia c Discipline of Obstetrics and Gynaecology, The University of Queensland, Herston, 4006 Brisbane, Australia b
a r t i c l e i n f o
a b s t r a c t
Article history: Accepted 19 April 2013
Since its discovery, transthyretin (TTR) has been regarded as an important hepatically derived protein carrier of thyroid hormones and retinol in blood. However, in more recent years it has been shown that TTR has other important functions. TTR is abundant in cerebrospinal fluid, where it may be involved in transport of thyroid hormones into the brain. TTR derived amyloid is associated with diseases such as senile systemic amyloidosis, familial amyloid polyneuropathy and familial amyloid cardiomyopathy. Recently, synthesis, secretion and uptake of TTR by human placenta have been reported. TTR appears to play an important role in the delivery of maternal thyroid hormone to the developing fetus. This review explores the various proposed roles of TTR and more recent findings on TTR synthesis and expression in the placenta. Crown Copyright Ó 2013 Published by Elsevier Ltd. All rights reserved.
Keywords: Transthyretin Placenta Thyroid hormone
1. Introduction It has become increasingly apparent that transthyretin (TTR) has roles that extend beyond those of a transporter of thyroid hormone and retinol in the serum. In this review we outline the many roles of TTR in different tissues before focussing on the more recently discovered placental synthesis, secretion and uptake of TTR. We highlight the potential importance of TTR during early fetal development and the additional research required in this area.
2. Transthyretin Transthyretin (TTR) formerly known as pre-albumin, was first discovered in 1942 both in human cerebrospinal fluid [1] and blood [2]. The term pre-albumin was used because TTR migrated ahead of albumin during electrophoresis. The name transthyretin was introduced in 1981 to reflect the protein’s roles in the transport (trans-) of thyroid hormone (-thy-) and retinol (-retin) [3]. TTR is derived from a gene duplication event of the Transthyretin-like protein gene. Transthyretin-like protein hydrolyses 5-hydroxyisourate in the purine catalytic pathway and is present in most organisms. TTR seems to have developed early in vertebrate evolution and is highly conserved amongst many animal
* Corresponding author. Conjoint Endocrine Laboratory, Royal Brisbane and Women’s Hospital, 300 Herston Rd, Herston, 4029 Brisbane, Queensland, Australia. Tel.: þ61 7 3362 0495; fax: þ61 7 3636 8842. E-mail address: [email protected] (K.A. Landers).
species including human, mouse, sheep, rat, fish, rabbit, lizard and chicken [4]. 2.1. Structure TTR is a 55 kDa homotetrameric protein comprising four identical 14 kDa subunits [5,6]. Approximately 45% of the amino acids in the TTR monomer are arranged into eight b-strands, names A through H, connected by loops, which result in a classic B barrel conformation [5]. Only 5% of amino acid residues in the monomer are in a short a-helix [7]. Dimers of TTR are composed of a pair of twisted eight-stranded b-sheets. The association of two dimers gives a tetrameric structure. The strength of the interactions identified between the monomers (resulting in a dimer) and between the dimers (forming a tetramer) suggests that the dimer rather than the monomer or tetramer is the most stable unit of the TTR structure [8]. The TTR tetramer is stable between pH 3.5e12 and has the ability to assemble subunits of different TTR molecules to form hybrid tetramers. 2.2. Function The main recognised function of TTR is the transport of thyroid hormone and retinol throughout the body. Thyroid hormone is extremely hydrophobic and is carried in blood bound to three hepatically secreted thyroid hormone binding proteins, thyroxine binding globulin (TBG), TTR and albumin. TBG has the highest affinity for thyroxine (T4) (affinity constant, Ka ¼ 1.0 1010M1), followed by TTR (7.0 107 M1) and albumin (7.0 105 M1). TBG
0143-4004/$ e see front matter Crown Copyright Ó 2013 Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.placenta.2013.04.013
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carries 65% of circulating T4 in the blood stream, whilst TTR transports 15% of T4 [9]. In contrast, TTR is the main carrier of T4 in the cerebrospinal fluid (CSF) [10]. TTR in tetrameric form has two thyroid hormone binding sites, but only one binding site is occupied under physiological conditions [11] due to negative co-operativity [12]. Tetrameric TTR has four binding sites for retinol binding protein (RBP) however, due to steric hindrance, a maximum of two molecules can bind per tetramer [13]. Under physiological conditions the TTR tetramer binds one RBP molecule only. RBP is synthesised in endoplasmic reticulum of the liver, where it binds retinol. The RBP-retinol complex binds TTR before it is secreted into plasma. The majority of retinol is delivered to cells via the TTR-RBP-retinol complex. Retinoids (retinol and its derivatives) control many biological functions such as vision, reproduction, development, growth and immunity [14]. In pregnancy retinoids are crucial for the mother’s health, maintenance of placenta and the developing embryo [15]. A recent functional study of TTR has demonstrated that it has protease activity. A small percentage of TTR circulates in blood bound to Apolipoprotein (Apo) A-1 and acts as a protease [16]. In vitro TTR was able to proteolytically cleave the carboxyl-terminal domain of Apo-A1. Only a small fraction of TTR is proteolytically active. Proteolytic TTR has also been shown to promote neurite outgrowth [17] suggesting a role in the nervous system and to prevent amyloid beta fibril formation, which accumulates in Alzheimer’s disease [18]. Other ligands of TTR include plant flavonoids [19], lysosomeassociated membrane protein (LAMP-1) [20] and a number of synthetic ligands including hydroxylated polychlorinated biphenyls [21], brominated flame-retardants [22] and non-steroidal anti-inflammatory drugs [23]. 2.3. Diseases associated with dysfunctional TTR Amyloid fibrils of TTR are the main constituent of senile systemic amyloidosis (SSA), familial amyloid polyneuropathy (FAP), familial amyloid cardiomyopathy (FAC) and central nervous system-associated amyloidosis (CNSA). SSA affects 25% of people over the age of 80 years and results from deposition of mainly wildtype TTR predominantly in cardiac tissue [24]. Mutated TTR variants lead to familial forms of amyloidosis such as FAP, FAC and CNSA. Familial amyloidosis is inherited in an autosomal dominant manner and can arise from one of over 100 mutated TTR variants that destabilise the TTR tetramer [25]. FAP is associated with progressive sensorimotor polyneuropathy, whilst FAC occurs later in life [26,27]. CNSA is also late-onset and due to amyloid found in the leptomeninges of the brain [28] and can be associated with dementia and ataxia [29]. Decreased levels of TTR have been observed in CSF of Alzheimer’s patients, where TTR is thought to prevent formation of the characteristic amyloid beta plaques [18]. CSF TTR levels are decreased in Alzheimer’s patients [30] and negatively correlate with degree of dementia [31]. Dysregulated placental TTR has been found in cases of intrauterine growth restriction and severe early onset preeclampsia [32]. While a causative role of TTR in preeclampsia has been postulated [33] there is little evidence for this. It is well known that insufficient levels of thyroid hormone during development leads to irreversible brain damage [34], even slight alterations in thyroid hormone levels during the first 12 weeks of gestation can result in reduced IQ [35]. Reduced levels of thyroid hormone in adults results in a myriad of symptoms including depression [36]. Interestingly, patients with depression have reduced levels of TTR [37,38] and TTR knockout mice have been shown to develop depressive-like behaviour [39].
Animal studies have also suggested that TTR has a role in behaviour, cognition and nerve regeneration [40]. 2.4. Synthesis and secretion TTR synthesis has been identified in the liver [41], choroid plexus [10], yolk sac [42], placenta [43], pancreas [44] and intestine [45] of humans. In other species, heart, skeletal muscle, stomach, spleen, the meninges [46], retinal pigment epithelia [47] and ciliary pigment epithelia [48] synthesise TTR. Liver and choroid plexus are the most abundant and well-described sites of TTR synthesis in humans and it is now clear that TTR is a product of human placenta. TTR synthesised by hepatocytes is secreted basally into the blood stream (0.2e0.25 mg/ml) [49]. This circulating pool of TTR contributes to the distribution of hydrophobic thyroid hormones in the blood stream [50]. In choroid plexus TTR is synthesised by the epithelial cells [10] and secreted apically into the CSF [51]. Choroid plexus has the highest concentration of TTR mRNA in the body and TTR accounts for 12% of all proteins synthesised. The secretion of TTR into ventricles is dependant on synthesis of new protein [52]. In CSF, 80% of T4 is bound to TTR whereas only 15% of T4 is bound to TTR in serum [10]. In rodents, it is proposed that newly synthesised TTR binds to T4 either in CP or after secretion into the CSF, the TTRT4 complex is then transported to the brain parenchyma [53,54]. It is yet to be determined whether this is true in humans. High levels of TTR have been observed in fetal serum as early as 13 weeks gestation at a time when fetal liver TTR mRNA expression is very low [41]. More recently it was discovered that TTR expression localised to placental trophoblasts [43]. Furthermore, TTR mRNA and protein are expressed as early as 6 weeks gestation in placental tissue and demonstrate significant time dependent linear increases in early pregnancy (6e13 weeks). From 13 to 17 weeks gestation both TTR mRNA and protein levels plateau and are similar to levels at term [55]. TTR secreted from polarised trophoblasts is mostly apical into the maternal circulation, with some secreted from the basal membrane [56]. This was confirmed in experiments using dually perfused placental lobules where newly synthesised TTR was secreted into both the maternal and fetal circuits [57]. One hundred times more TTR was secreted into the maternal compared with the fetal circulation. 2.5. Internalisation Studies of TTR internalisation in hepatomas and primary hepatocytes suggested that hepatic TTR uptake is mediated by a receptor of the low-density lipoprotein (LDL) receptor family [58]. TTR internalisation in renal cells involved a receptor identified as megalin (LRP2), an endocytic multi-ligand receptor of the LDL receptor family [59]. Furthermore, in sensory neurons of mice TTR internalisation is clathrin dependent, and megalin mediated [60] Internalisation of TTR by trophoblasts is a recent discovery. In the presence of T4, TTR uptake is increased [56] a phenomenon that Divino and Schussler as well as Sousa and Saraiva observed in hepatoma cells [61,62]. T4 binding stabilised the TTR tetramer and increased TTR internalisation [56] suggesting that the TTR-T4 tetramer is endocytosed. Interestingly, tetramer formation induced by the TTR stabilisers diflunisal and iodo-diflunisal did not increase internalisation [56]. Hence, it was proposed that placental TTR binds maternal T4 and is internalised by trophoblast cells. The ‘free hormone hypothesis’ was first proposed by Recant and Riggs in 1952 and states that the biological activity of a hormone in vivo can only be predicted by its unbound form because only free hormones are taken up by cells [63,64]. Clearly a transthyretin-mediated cell uptake of T4 challenges this idea.
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Using mathematical modelling and experiments with perfused placental lobules, a model was proposed for the synthesis, secretion and uptake of TTR in the placenta [57]. The best-fit model suggested that TTR was secreted into the maternal circulation where it could be taken back up into the placenta and subsequently secreted into the fetal circuit. Internalisation of TTR from the maternal circuit of the perfused placental lobule was low, however T4 was absent from the experiment and this may have reduced internalisation. High local concentrations of TTR at the maternaleplacental interface may bind maternal T4 for shuttling to the fetal capillaries. Interestingly, Alexa-labelled TTR (in the presence of T4) could be demonstrated in fetal capillaries in early (14e15 weeks gestation) and late (38e40 weeks gestation) placental explants [57]. 2.6. Regulation Costa and Grayson discovered that TTR gene expression in hepatocytes is regulated by two 50 UTR regions, a proximal promoter region and a distal enhancer region [65]. These two regions contain binding sites for HNF, CCAAT/enhancer binding protein (C/EBP) and AP-1/cjun that contribute to transcriptional regulation in hepatocytes. Within the choroid plexus, the HNFs are absent and it is thought TTR is regulated by transcription factors that are closely related to the HNFs [66]. This demonstrates that there is tissue specific regulation. In placenta the transcriptional binding proteins, HNF-3 (or FOXa2), C/ EBP and AP-1 are expressed throughout gestation and are involved in activating transcription of a number of genes important for fetal development [67,68]. Patel et al. (2012) reported an increase in TTR promoter activity in choriocarcinoma cells when cells were cultured at 1% oxygen (hypoxic conditions) [69]. Interestingly, C/EBP and AP-1 are also up-regulated in hypoxic conditions and interact with hypoxia-inducible factor-1a (HIF-1a) [70]. Furthermore, TTR mRNA and protein expression increased in choriocarcinoma cells and primary trophoblast cells cultured at 1% oxygen compared with cells cultured at 8% or 21% oxygen [71]. This may be physiologically important considering during the first trimester of pregnancy the placenta is relatively hypoxic with oxygen levels of 1e3% (15e18 mm Hg) at the time of implantation [72,73]. Following placental development and invasion into the maternal decidua (8e10 weeks) oxygen levels rise to 3e5% (18 mm Hg) and by the end of the first trimester (12e13 weeks) oxygen concentrations are at 7e10% (60 mm Hg) and remain here until birth [72]. However, this was not reflected in the ontogenic data collected on TTR mRNA and protein measured in placenta tissue, which increased with gestation (i.e. as oxygenation increased) [69]. This highlights the complexity of the placenta and the many factors regulating gene transcription and translation within this tissue. 3. Conclusion Clearly TTR has many different roles that go beyond that of a serum carrier of thyroid hormone and retinol. Since our discovery of TTR synthesis in the placenta we have reported that it is secreted predominantly into the maternal circulation where it can also be taken back up by trophoblasts in the presence of T4. During pregnancy the fetus starts to produce thyroid hormone from approximately 12 weeks gestation. Prior to 12 weeks gestation fetal thyroid hormone supply is from the mother, which can continue throughout pregnancy if required. The mechanisms underlying this maternalefetal transfer of thyroid hormone are poorly understood. It is known that the placenta has high levels of deiodinase type 3 activity which inactivates T4 to its inactive form rT3. The presence of TTR in the placenta as early as 6 weeks gestation may play an important role in binding maternal T4, preventing deiodination and delivering it to fetal capillaries.
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TTR appears to be internalised by trophoblasts in its tetrameric form in the presence of T4, suggesting TTR-T4 are internalised as a complex. Further research is required to establish the nature of this internalisation and which membrane transporters may be involved. Internalisation of T4 bound to a carrier protein (TTR) would challenge the ‘free hormone hypothesis’ [63,64] and suggests that there are other pathways involved in cellular uptake of T4. One of the main functions of TTR in the liver and choroid plexus is to ensure even distribution of thyroid hormone either in the blood or brain, respectively. It will be important to investigate if TTR plays a similar role in the placenta or maternal compartments of the placenta. Regulation of TTR in liver and choroid plexus is very different. Liver TTR expression is down-regulated during an acute phase response [74] whilst choroid plexus TTR is not affected under the same conditions [66] preventing detrimental disruptions in the thyroid hormone economy of the brain. Identifying how TTR is regulated in the placenta throughout gestation is of interest as current evidence suggests it plays a role in the handling of T4 during this time. Finally, TTR has been highly conserved throughout evolution, mutations in the gene are heterozygous and there have been no reports of a human with a gene deletion of TTR. All of these points suggest that TTR plays a pivotal role in the human body. Further research on the roles of TTR is essential in order for us to fully understand this remarkable protein. References [1] Kabat EA, Moore DH, Landow H. An electrophoretic study of the protein components in cerebrospinal fluid and their relationship to the serum proteins. Journal of Clinical Investigation 1942;21(5):571e7. [2] Seibert FB, Nelson JW. Electrophoretic study of the blood protein response in tuberculosis. Journal of Biological Chemistry 1942;143(1):29e38. [3] Nomenclature Committee of IUB (NC-IUB) IUB-IUPAC Joint Commission on Biochemical Nomenclature (JCBN). Newsletter 1981. Journal of Biological Chemistry 1981;256(1):12e4. [4] Power DM, Elias NP, Richardson SJ, Mendes J, Soares CM, Santos CR. Evolution of the thyroid hormone-binding protein, transthyretin. General and Comparative Endocrinology 2000;119(3):241e55. [5] Blake CC, Geisow MJ, Oatley SJ, Rerat B, Rerat C. Structure of prealbumin: secondary, tertiary and quaternary interactions determined by Fourier refinement at 1.8 A. Journal of Molecular Biology 1978;121(3):339e56. [6] Blake CC, Swan ID, Rerat C, Berthou J, Laurent A, Rerat B. An x-ray study of the subunit structure of prealbumin. Journal of Molecular Biology 1971;61(1):217e24. [7] Blake CC, Geisow MJ, Swan ID, Rerat C, Rerat B. Structure of human plasma prealbumin at 2e5 A resolution. A preliminary report on the polypeptide chain conformation, quaternary structure and thyroxine binding. Journal of Molecular Biology 1974;88(1):1e12. [8] Robbins J, Cheng SY, Gershengorn MC, Glinoer D, Cahnmann HJ, Edelnoch H. Thyroxine transport proteins of plasma. Molecular properties and biosynthesis. Recent Progress in Hormone Research 1978;34:477e519. [9] Schreiber G. The evolutionary and integrative roles of transthyretin in thyroid hormone homeostasis. The Journal of Endocrinology 2002;175(1):61e73. [10] Herbert J, Wilcox JN, Pham KT, Fremeau Jr RT, Zeviani M, Dwork A, et al. Transthyretin: a choroid plexus-specific transport protein in human brain. The 1986 S. Weir Mitchell award. Neurology 1986;36(7):900e11. [11] Wojtczak A, Cody V, Luft JR, Pangborn W. Structures of human transthyretin complexed with thyroxine at 2.0 A resolution and 30 ,50 -dinitro-N-acetyl-Lthyronine at 2.2 A resolution. Acta Crystallographica Section D, Biological Crystallography 1996;52(Pt 4):758e65. [12] Ferguson RN, Edelhoch H, Saroff HA, Robbins J, Cahnmann HJ. Negative cooperativity in the binding of thyroxine to human serum prealbumin. Preparation of tritium-labeled 8-anilino-1-naphthalenesulfonic acid. Biochemistry 1975;14(2):282e9. [13] Monaco HL, Rizzi M, Coda A. Structure of a complex of two plasma proteins: transthyretin and retinol-binding protein. Science 1995;268(5213): 1039e41. [14] Blomhoff R, Blomhoff HK. Overview of retinoid metabolism and function. Journal of Neurobiology 2006;66(7):606e30. [15] Clagett-Dame M, DeLuca HF. The role of vitamin A in mammalian reproduction and embryonic development. Annual Review of Nutrition 2002;22:347e81. [16] Liz MA, Faro CJ, Saraiva MJ, Sousa MM. Transthyretin, a new cryptic protease. The Journal of Biological Chemistry 2004;279(20):21431e8. [17] Liz MA, Fleming CE, Nunes AF, Almeida MR, Mar FM, Choe Y, et al. Substrate specificity of transthyretin: identification of natural substrates in the nervous system. The Biochemical Journal 2009;419(2):467e74.
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