Impact of Oatp1c1 Deficiency on Thyroid Hormone Metabolism and Action in the Mouse Brain

Abstract

Organic anion-transporting polypeptide 1c1 (Oatp1c1) (also known as Slco1c1 and Oatp14) belongs to the family of Oatp and has been shown to facilitate the transport of T(4). In the rodent brain, Oatp1c1 is highly enriched in capillary endothelial cells and choroid plexus structures where it may mediate the entry of T(4) into the central nervous system. Here, we describe the generation and first analysis of Oatp1c1-deficient mice. Oatp1c1 knockout (KO) mice were born with the expected frequency, were not growth retarded, and developed without any overt neurological abnormalities. Serum T(3) and T(4) concentrations as well as renal and hepatic deiodinase type 1 expression levels were indistinguishable between Oatp1c1 KO mice and control animals. Hypothalamic TRH and pituitary TSH mRNA levels were not affected, but brain T(4) and T(3) content was decreased in Oatp1c1-deficient animals. Moreover, increased type 2 and decreased type 3 deiodinase activities indicate a mild hypothyroid situation in the brain of Oatp1c1 KO mice. Consequently, mRNA expression levels of gene products positively regulated by T(3) in the brain were down-regulated. This central nervous system-specific hypothyroidism is presumably caused by an impaired passage of T(4) across the blood-brain barrier and indicates a unique function of Oatp1c1 in facilitating T(4) transport despite the presence of other thyroid hormone transporters such as Mct8.

Zebrafish as a Model for Monocarboxyl Transporter 8-Deficiency

“…In contrast, in rodents, MCT8 mRNA and protein were observed in the blood-brain barrier (53), suggesting that MCT8 is not directly involved in TH transport across the blood-brain barrier in non-mammalian vertebrates. Our expression studies suggest that, as is the case in mammals (6,12,48), OATP1C1 can function in zebrafish blood-brain barrier, and MCT8 can regulate the transport of THs from the blood to the nervous system in distinct regions.…”

“…Although mct8 was widely expressed in the CNS, oatp1c1 expression was restricted to vasculature structures within the brain. Similarly, in rodents, oatp1c1 shows a strong expression in brain endothelial cells and in choroid plexus structures (6,12,45). MCT10, which is thought to act in the liver, intestine, kidneys, and growth plate chondrocytes in mammals (6,46,47), was observed in the liver and the trigeminal ganglia in zebrafish.…”

“…MCT10, which is thought to act in the liver, intestine, kidneys, and growth plate chondrocytes in mammals (6,46,47), was observed in the liver and the trigeminal ganglia in zebrafish. Recently, OATP1C1 was implicated as compensating for the lack of MCT8 in MCT8-knock-out mice (12,48). The distinct expression patterns of oatp1c1 and mct10 FIGURE 6.…”

“…Biochemical studies suggested that the transport of T 3 , but not its precursor, thyroxine (T 4 ), is impeded in MCT8-deficient mice, thus additional TH transporters, such as OATP1C1 and MCT10, might compensate for MCT8 deficiency in rodents (11,12). Clearly, the establishment of additional MCT8-deficient vertebrate models that mimic the pathophysiological condition of AHDS patients is required to complement the mouse model and to better understand the role of MCT8.…”

Thyroid hormone and the central control of homeostasis

“…As genetic and neuroanatomical techniques have greatly advanced during the recent years, we are now equipped with the right tools to address these questions -in particular, the availability of several Cre mouse strains with Figure 2 Targeting thyroid hormone signalling in the brain. Several different molecules such as transporters (circle), deiodinases (triangle) and receptors (pacman) are involved in controlling thyroid hormone actions in the brain , Dumitrescu et al 2006, Trajkovic et al 2007, Wallis et al 2010, Mayerl et al 2012. BBB, blood brain barrier; Dio2/3, deiodinase type II or III; MCT8, monocarboxylate transporter 8; Oatp1c1, organic anion transporting polypeptide 1c1; TR, thyroid hormone receptor.…”