Role of the murine thyroid hormone transporters Mct8 and Oatp1c1 in the cardiovascular and thermoregulatory systems

Thyroid hormones (TH) are essential for cardiovascular functions and thermoregulation, both by peripheral as well as central mechanisms. Both TH deficiency and TH excess represent pathological conditions that are accompanied by a vast array of clinical manifestations (e.g. bradycardia/tachycardia or heat/cold intolerance). With the recent identification of specific TH transporters, the general concept of TH action has to be reevaluated. Since TH transporters are essential for mediating the cellular entry and efflux of TH, alterations in TH transporter activity can greatly affect the tissue-specific thyroidal state.           

The monocarboxylate transporter 8 (MCT8) represents the most specific TH transporter. In humans and rodents, MCT8 is expressed in many organs, in particular the brain, and can mediate the cellular uptake and efflux of TH. Its pathophysiological significance became evident with the identifications of patients carrying inactivating mutations in the X-linked SLC16A2 gene. All affected individuals exhibit a uniform syndrome (also known as Allan-Herndon Dudley syndrome (AHDS)) comprising a severe form of psychomotor retardation with pronounced proximal hypotonia, spastic or dystonic quadriplegia and lack of speech development. In mice, however, a second TH transporter (Oatp1c1) can compensate for the loss of MCT8. Consequently, double KO mice for MCT8 and Oatp1c1 represent a very good animal model for AHDS. In this project, we aim to study cardiovascular function and thermoregulation (heat loss by the tail as well as thermogenesis in BAT) in this AHDS model system.

This project is a collaboration with Dr. Heike Heuer at the IUF Düsseldorf. Together with Dr. Heuer we have had several publications on TH transporters and especially the MCT8 KO mice. In these studies, we established that Oatp1c1 can partially compensate for the loss of MCT8, leading to the double KO mouse model for AHDS. Moreover, we established that these mice lack any import of TH into the brain, making the animals a valuable model system to study central hypothyrodism in the presence of almost normal levels of circulating hormone.

References

Trajkovic-Arsic M, Visser TJ, Darras VM, Friesema ECM, Schlott B, Mittag J, Bauer K, Heuer H: “Consequences of MCT8 deficiency for renal transport and metabolism of thyroid hormones” Endocrinology 2010 Feb;151(2):802-9

Trajkovic M, Visser TJ, Mittag J, Horn S, Lukas J, Darras V, Raivich G, Bauer K, Heuer H: “Abnormal Thyroid Hormone Metabolism in Mice Lacking the Monocarboxylate Transporter 8” Journal of Clinical Investigation 2007 Mar 1;117(3):627-635

Publications

Oelkrug, R., Herrmann, B., Geissler, C., Harder, L., Koch, C., Lehnert, H., Oster, H., Kirchner, H., and Mittag, J.: Dwarfism and insulin resistance in male offspring caused by α1-adrenergic antagonism during pregnancy. Mol Metab, vol. PII: S2212-8778(17), pp. 30367-8, 2017, doi.org/10.1016/j.molmet.2017.06.016