Transthyretin as a Thyroid Hormone Carrier: Function Revisited

Abstract

Thyroid hormones are essential for normal mammalian development and for normal metabolism. Thyroxine (T4) is the principal product synthesized by the thyroid follicles, and triiodothyronine (T3), the biologically active hormone, derives mainly from tissue T4 deiodination. More than 99% of the circulating hormone is bound to plasma proteins, mainly to thyroxine-binding globulin, transthyretin and albumin in man, and to transthyretin and albumin in rodents. The role of plasma proteins in the transport of hormones to target tissues has, for a long time, been controversial. The liver and the choroid plexus are the major sites of transthyretin synthesis, tissues from which transthyretin is secreted into the blood and the cerebrospinal fluid, respectively. Transthyretin has been proposed to mediate thyroid hormone transfer into the tissues, particularly into the brain across the choroid-plexus-cerebrospinal fluid barrier. Studies in a transthyretin-null mice strain have shown conclusively that transthyretin is not indespensable for thyroid hormones' entry into the brain and other tissues, nor for the maintenance of an euthyroid status. An euthyroid status is also observed in man totally deprived of thyroxine-binding globulin and in rats without albumin. Taken together, these results exclude dependence of thyroid hormone homeostasis on any major plasma carrier per se. This evidence agrees with the free hormone hypothesis which states that the biologically significant fraction, that is taken up by the tissues, is the free circulating hormone.

Developmental neurotoxicity of polybrominated diphenyl ether (PBDE) flame retardants

“…Whether the hypothesized mechanisms of PBDEinduced hypothyroxemia (induction of UDPGT and interference with TTR) are operational in humans remains to be determined. For example, as the major T 4 transporter in humans is believed to be a thyroid-binding globulin (TBG), followed by TTR and albumin (Schussler, 2000;Palha, 2002), the impact of PBDE binding to TTR may be lower in humans than in rodents. Furthermore, hydroxylated PCBs bind to TBG with much lower affinity than to TTR (Lans et al 1994), and the same may be true for hydrolated PBDEs.…”

“…Furthermore, hydroxylated PCBs bind to TBG with much lower affinity than to TTR (Lans et al 1994), and the same may be true for hydrolated PBDEs. TTR may still facilitate the transport of OH-PBDEs in the brain (Meerts et al 2000), though it has been shown that TTR is not indispensable for T 4 entry into the brain (Palha, 2002). Biochemical studies on direct effects of PBDE on the developing brain have yet to provide convincing evidence of precise mechanisms, though some indications (e.g.…”

Transthyretin is not necessary for thyroid hormone metabolism in conditions of increased hormone demand

“…This hypothesis states that the biologically important pool of hormone in the circulation is in the free form (Mendel 1989). The role of carrier proteins in hormone delivery to tissues has been a matter of great debate (Schreiber et al 1990, Palha 2002, Schreiber 2002. Individually, transport proteins might be redundant and part of a back-up mechanism for other carriers; they might not be essential but still contribute to hormone delivery to particular tissues, or they might represent important storage/buffer reservoirs required under conditions of increased or decreased hormone demand.…”

Expression and uptake of the thyroxine-binding protein transthyretin is regulated by oxygen in primary trophoblast placental cells

“…Exposure to low oxygen levels also resulted in increased cellular uptake of TTR by primary trophoblasts, validating the use of JEG-3 cells as a model for examining interactions of TTR synthesis, secretion and uptake when exposed to different oxygen levels (Patel et al 2010a). TTR is a 56 kDa homotetrameric protein found in serum where it transports T 4 and retinol (Blake et al 1971, Palha 2002. TTR is produced and secreted into the circulation by liver (Hamilton & Benson 2001).…”