Understanding the Hypothalamus-Pituitary-Thyroid Axis in Mct8 Deficiency

Abstract

Thyroid hormone (TH) metabolism and action via binding to nuclear receptors are intracellular events that require the passage of TH across the plasma membrane. This process is mediated by specific TH transporters of which the monocarboxylate transporter 8 (Mct8) has received major attention. Mct8 is highly expressed in different tissues such as liver, kidney, thyroid, pituitary and brain. In humans, inactivating mutations of the MCT8 gene (SLC16A2) are associated with severe forms of psychomotor retardation and abnormal TH serum levels (Allan-Herndon-Dudley syndrome). Surprisingly, Mct8 knockout (ko) mice do not exhibit overt neurological symptoms but fully replicate the unusual serum TH profile with highly increased serum T₃ in the presence of low serum T₄. In order to evaluate the underlying mechanisms for these abnormalities, TH transport and metabolism have been intensively studied in different tissues of Mct8 ko mice. Here, we summarize the observed changes within the hypothalamus-pituitary-thyroid axis that result in altered TH production and secretion. Although analysis of Mct8 ko mice has greatly expanded our knowledge, many open questions still remain to be addressed in order to define the tissue- and cell-specific role of this important TH transporter.

Thyroid Hormone Transporters

“…More information is available regarding the localization and function of MCT8 in the human and mouse thyroid gland, where MCT8 is present at the basolateral membrane of follicular epithelial cells (206,207). Therefore, it is conceivable that a global lack of MCT8 affects a proper function of the HPT axis on all levels as best illustrated in Mct8-ko mice (426).…”

The Amino Acid Transporter Mct10/Tat1 Is Important to Maintain the TSH Receptor at Its Canonical Basolateral Localization and Assures Regular Turnover of Thyroid Follicle Cells in Male Mice

“…Studies have shown that despite the unusual pattern of TH serum concentrations in Mct8 deficiency [ 10 , 11 , 15 , 27 ], the HPT axis is deregulated differently in Mct8 −/y mice of different ages, namely TSH serum concentrations are significantly [ 10 , 27 ] or only moderately enhanced in Mct8 deficiency [ 11 , 15 , 16 ]. We report in the present study that serum TSH concentrations in Ctsk −/− , Ctsk −/− / Mct10 −/− , Ctsk −/− / Mct8 −/y , and Ctsk −/− / Mct8 −/y / Mct10 −/− mice showed no significant changes when compared to WT controls (see, Figure 1 ).…”

“…On the contrary, genotypes featuring upregulation of Mct8 such as that observed in Ctsk −/− mice [ 8 ] result neither in altered thyroid functional nor morphological phenotypes [ 13 , 14 ]. Although it is known that serum TSH concentrations remain unaffected in Ctsk −/− mice [ 14 ] and are significantly [ 10 ] or moderately elevated in Mct8 deficiency [ 11 , 15 , 16 ] in young or adult mice, respectively, no information is available on the outcomes of TSH receptor signaling in genotypes where Mct8 is lacking (i.e., Mct8 −/y ) or upregulated (i.e., Ctsk −/− ). Moreover, in-depth knowledge on whether differences in TSH receptor localization can impact signaling, and, consequently, thyroid gland morphology and physiology, is still at the beginning of our understanding [ 17 , 18 ].…”

Tissue-Specific Function of Thyroid Hormone Transporters: New Insights from Mouse Models

“…These data unequivocally demonstrate that T3 can enter different target cells independent of Mct8. High tissue T3 content in turn stimulates increased expression of the TH metabolizing enzyme deiodinase type 1 (Dio1) that further elevates local T3 concentrations and thereby initiates a vicious circle [13,14]. Interestingly, mice with a concomitant inactivation of Mct8 and Dio1 exhibited a normalization of T3 serum levels indicating that increased Dio1 activity is indeed a major contributor to the elevated serum T3 characteristic for Mct8 deficiency [15].…”