Expression of the Thyroid Hormone Transporters Monocarboxylate Transporter-8 (SLC16A2) and Organic Ion Transporter-14 (SLCO1C1) at the Blood-Brain Barrier

Abstract

Thyroid hormones require transport across cell membranes to carry out their biological functions. The importance of transport for thyroid hormone signaling was highlighted by the discovery that inactivating mutations in the human monocarboxylate transporter-8 (MCT8) (SLC16A2) cause severe psychomotor retardation due to thyroid hormone deficiency in the central nervous system. It has been reported that Mct8 expression in the mouse brain is restricted to neurons, leading to the model that organic ion transporter polypeptide-14 (OATP14, also known as OATP1C1/SLCO1C1) is the primary thyroid hormone transporter at the blood-brain barrier, whereas MCT8 mediates thyroid hormone uptake into neurons. In contrast to these reports, we report here that in addition to neuronal expression, MCT8 mRNA and protein are expressed in cerebral microvessels in human, mouse, and rat. In addition, OATP14 mRNA and protein are strongly enriched in mouse and rat cerebral microvessels but not in human microvessels. In rat, Mct8 and Oatp14 proteins localize to both the luminal and abluminal microvessel membranes. In human and rodent choroid plexus epithelial cells, MCT8 is concentrated on the epithelial cell apical surface and OATP14 localizes primarily to the basal-lateral surface. Mct8 and Oatp14 expression was also observed in mouse and rat tanycytes, which are thought to form a barrier between hypothalamic blood vessels and brain. These results raise the possibility that reduced thyroid hormone transport across the blood-brain barrier contributes to the neurological deficits observed in affected patients with MCT8 mutations. The high microvessel expression of OATP14 in rodent compared with human brain may contribute to the relatively mild phenotype observed in Mct8-null mice, in contrast to humans lacking functional MCT8.

Molecular aspects of thyroid hormone transporters, including MCT8, MCT10, and OATPs, and the effects of genetic variation in these transporters

“…For instance, in a recent report Roberts et al (2008) showed the expression of OATP1C1 is higher in rodents compared with human brain. However, due to the high level of homology in structure and substrate specificity between rodent and human OATP1C1, it seems plausible that OATP1C1 is also important for T 4 uptake in the human brain.…”

“…In the mouse brain, MCT8 is expressed not only in neurons but also in capillaries and the choroid plexus (Heuer et al 2005, Roberts et al 2008. The importance of MCT8 in the blood-brain barrier and in the blood-cerebral spinal fluid (CSF) barrier is strongly suggested by the almost complete block in brain T 3 uptake in MCT8 knockout mice (Trajkovic et al 2007).…”

“…Brain T 4 uptake is not affected in MCT8 knockout mice, which is explained by the expression of the T 4 transporter OATP1C1 in brain capillaries. Recently, Roberts et al (2008) have shown that OATP1C1 is strongly expressed in mouse and rat cerebral microvessels, but not in human microvessels. This high expression of OATP1C1 in microvessels in rodents compared with human brain may contribute to the relatively mild phenotype observed in MCT8-null mice, in contrast to humans lacking functional MCT8.…”

Tissue-specific effects of mutations in the thyroid hormone transporter MCT8

“…However, brain T3 uptake is probably largely determined by transport across the blood-brain barrier (BBB) and/or the blood-CSF barrier (BCB) and indeed MCT8 is importantly expressed in brain capillaries and in the choroid plexus (7,13). The lack of effect of Mct8 inactivation on brain uptake of T4, which is also a substrate for MCT8, may be explained by assuming that T4 is largely transported across the BBB and BCF by OATP1C1 (7,13).…”

Thyroid hormone transporters and deiodinases in the developing human hypothalamus

“…Expression of OATP1C1 is restricted to specific areas of the adult brain, in particular in the capillary wall and in the choroid plexus, whereas MCT8 and MCT10 are widely expressed throughout the body including the brain (8,10,11,12,13,14). From the three deiodinases, types 1, 2, and 3 (D1, D2, and D3), D2 and D3 are particularly important for the regulation of intracellular TH levels in the brain (15).…”