Differences in Mouse Hepatic Thyroid Hormone Transporter Expression with Age and Hyperthyroidism

Abstract

Background: Clinical features of thyroid dysfunction vary with age, and an oligosymptomatic presentation of hyperthyroidism is frequently observed in the elderly. This suggests age modulation of thyroid hormone (TH) action, which may occur, for example, by alterations in TH production, metabolism and/or TH action in target organs. Objectives: In this paper, we address possible changes in TH transporter expression in liver tissues as a mechanism of age-dependent variation in TH action. Methods: Chronic hyperthyroidism was induced in 4- and 20-month-old C57BL6/NTac male mice (n = 8-10) by intraperitoneal injections of 1 µg/g body weight <smlcap>L</smlcap>-thyroxine (T₄) every 48 h over 7 weeks. Control animals were injected with PBS. Total RNA was isolated from liver samples for analysis of the TH transporter and TH-responsive gene expression. TH concentrations were determined in mice sera. Results: Baseline serum free T₄ (fT₄) concentrations were significantly higher in euthyroid young compared to old mice. T₄ treatment increased total T₄, fT₄ and free triiodothyronine to comparable concentrations in young and old mice. In the euthyroid state, TH transporter expression was significantly higher in old than in young mice, except for Mct8 and Oatp1a1 expression levels. Hyperthyroidism resulted in upregulation of Mct10, Lat1 and Lat2 in liver tissue, while Oatp1a1, Oatp1b2 and Oatp1a4 expression was downregulated. This effect was preserved in old animals. Conclusion: Here, we show age-dependent differences in TH transporter mRNA expression in the euthyroid and hyperthyroid state of mice focusing on the liver as a classical TH target organ.

Reduced expression of thyroid hormone receptor β in human nonalcoholic steatohepatitis

“…Consequently, data on the local change in TH economy on the tissue level are highly relevant to understand the underlying causes and therapeutic consequences. Several studies on animal models are available, revealing decreased liver Slc16a2 and Dio1 expression in old rats (35), increased Slc10a1 but unaltered Slc16a2 transcripts in old mice (36) and lower DIO1 activities in several mouse models of aging (37). On the receptor level, no effect of age on Thra was observed, while a progressive increase in Thrb mRNA and total TRβ protein level was found in old rats; however, most remarkably, the nuclear levels of TRβ seemed to decline (35).…”

Sex-specific phenotypes of hyperthyroidism and hypothyroidism in mice

“…Chronic hyperthyroidism and hypothyroidism were induced as previously described [ 5 , 6 ]. Briefly, for hyperthyroidism, i.p.…”

Auto-Regulation of the Thyroid Gland Beyond Classical Pathways

“…In the following, we will discuss recent insights into thyroid auto-regulation, which we chose to define as the ability of thyrocytes to maintain regular functional activities throughout all life stages, but focusing on the adult state. Important conclusions can be drawn when thyroid functionality is challenged, e. g., by knockingout thyroid function-critical genes [22][23][24][25][26] or by specifically inducing thyroid dysfunction in animal models [27][28][29][30][31]. Knowledge on the complexity of molecules and pathways involved in thyroid auto-regulation is continuously growing as their intricate interconnections are displayed in such animal models by the many mild and more severe phenotypes in thyroid functionality (▶table 1).…”