SCHREIBER, G: The Evolutionary and Integrative Roles of Transthyretin in Thyroid Hormone Homeostasis

In larger mammals, thyroid hormone-binding plasma proteins are albumin, transthyretin (TTR) and thyroxine-binding globulin. Differing characteristically in affinities and release rates for thyroxine (T4) and triiodothyronine (T3), they form a “buffering” system counteracting thyroid hormone permeation from aqueous to lipid phases. Evolution led to important differences in the expression pattern of these three proteins in tissues. In adult liver, TTR is only made in eutherians and herbivorous marsupials. During development it is also made in tadpole and fish liver. More intense TTR synthesis than in liver is found in the choroid plexus of reptilians, birds, and mammals, but none in choroid plexus of amphibians and fish, i. e. species without a neocortex. All brain-made TTR is secreted into the cerebrospinal fluid, where it becomes the major thyroid hormone-binding protein. TTR synthesis intensity in choroid plexus parallels brain growth rate. TTR is only one component in a network of factors determining thyroid hormone distribution. This explains why, under laboratory conditions, TTR-knockout mice show no major abnormalities. The ratio of the affinity of TTR for T4 to that for T3 is higher in eutherians than in marsupials and birds. This favors T4 transport from blood to brain providing more substrate for conversion of the biologically less active T4 into the biologically more active T3 by the tissue-specific brain deiodinases. The amino acid sequences of fish and amphibian TTRs are very similar to those in mammals, suggesting that substantial TTR evolution occurred before the vertebrate stage. Open reading frames for TTR-like sequences already exist in C. elegans, yeast and E. coli genomes.