PUBLICATION
3,3',5-tri-iodothyroacetic acid (TRIAC) transporters
- Authors
- Chen, Z., Yildiz, S., Markova, B., de Rooij, L.J., Leeuwenburgh, S., Hamers, T., Peeters, R.P., Heuer, H., Meima, M.E., Visser, W.E.
- ID
- ZDB-PUB-240606-2
- Date
- 2024
- Source
- Thyroid : official journal of the American Thyroid Association 34(8): 1027-1037 (Journal)
- Registered Authors
- Keywords
- none
- MeSH Terms
-
- Animals
- Biological Transport
- Blood-Brain Barrier*/metabolism
- COS Cells
- Chlorocebus aethiops
- Humans
- Mice
- Mice, Knockout
- Monocarboxylic Acid Transporters*/genetics
- Monocarboxylic Acid Transporters*/metabolism
- Muscle Hypotonia/genetics
- Muscle Hypotonia/metabolism
- Muscular Atrophy
- Organic Anion Transporters/genetics
- Organic Anion Transporters/metabolism
- Symporters*/genetics
- Symporters*/metabolism
- Triiodothyronine*/analogs & derivatives
- Triiodothyronine*/metabolism
- X-Linked Intellectual Disability
- Zebrafish
- PubMed
- 38836423 Full text @ Thyroid
Citation
Chen, Z., Yildiz, S., Markova, B., de Rooij, L.J., Leeuwenburgh, S., Hamers, T., Peeters, R.P., Heuer, H., Meima, M.E., Visser, W.E. (2024) 3,3',5-tri-iodothyroacetic acid (TRIAC) transporters. Thyroid : official journal of the American Thyroid Association. 34(8):1027-1037.
Abstract
Introduction Thyroid hormone transporters are essential for thyroid hormones to enter target cells. Monocarboxylate transporter MCT8 is a key transporter and expressed at the blood-brain barrier, in neural cells and many other tissues. Patients with MCT8 deficiency have severe neurodevelopmental delays due to cerebral hypothyroidism and chronic sequelae of peripheral thyrotoxicosis. The T3 analog 3,3,5-triiodothyroacetic acid (TRIAC) rescued neurodevelopmental features in animal models mimicking MCT8 deficiency and improved key metabolic features in patients with MCT8 deficiency. However, the identity of the transporter(s) that facilitate TRIAC transport are unknown. Here, we screened candidate transporters that are expressed at the human blood-brain barrier and/or brain-cerebrospinal fluid barrier and known thyroid hormone transporters for TRIAC transport. Materials and methods Plasma membrane expression was determined by cell surface biotinylation assays. Intracellular accumulation of 1 nM TRIAC was assessed in COS-1 cells expressing candidate transporters in Dulbecco's phosphate buffered saline (DPBS)/0.1% glucose or Dulbecco's modified Eagle's medium (DMEM) with or without 0.1% bovine serum albumin (BSA). Expression of Slc22a8 was determined by fluorescent in situ hybridization (FISH) in brain sections from wild-type and Mct8/Oatp1c1 knock-out mice at postnatal day 12, 21 and 120. Results Fifty-nine plasma membrane transporters were selected for screening of TRIAC accumulation (n=40 based on expression at the human blood-brain barrier and/or brain-cerebrospinal fluid barrier and having small organic molecules as substrates; n=19 known thyroid hormone transporters). Screening of the selected transporter panel showed that 18 transporters facilitated significant intracellular accumulation of TRIAC in DPBS/0.1% glucose or DMEM in the absence of BSA. In the presence of BSA, substantial transport was noted for SLCO1B1 and SLC22A8 (in DPBS/0.1% glucose and DMEM) and SLC10A1, SLC22A6 and SLC22A24 (in DMEM). The zebrafish and mouse orthologues of these transporters similarly facilitated intracellular accumulation of TRIAC. Highest Slc22a8 mRNA expression was detected in mouse brain capillary endothelial cells and choroid plexus epithelial cells at early postnatal time points, but wasreduced at P120. Conclusions Human SLC10A1, SLCO1B1, SLC22A6, SLC22A8 and SLC22A24 as well as their mouse and zebrafish orthologues are efficient TRIAC transporters. These findings contribute to the understanding of TRIAC treatment in patients with MCT8 deficiency and animal models thereof.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping