3,5-T2 alters murine genes relevant for xenobiotic, steroid, and thyroid hormone metabolism

Abstract

The endogenous thyroid hormone (TH) metabolite 3,5-diiodo-l-thyronine (3,5-T 2 ) acts as a metabolically active substance affecting whole-body energy metabolism and hepatic lipid handling in a desirable manner. Considering possible adverse effects regarding thyromimetic action of 3,5-T 2 treatment in rodents, the current literature remains largely controversial. To obtain further insights into molecular mechanisms and to identify novel target genes of 3,5-T 2 in liver, we performed a microarray-based liver tissue transcriptome analysis of male lean and diet-induced obese euthyroid mice treated for 4 weeks with a dose of 2.5 µg/g bw 3,5-T 2 . Our results revealed that 3,5-T 2 modulates the expression of genes encoding Phase I and Phase II enzymes as well as Phase III transporters, which play central roles in metabolism and detoxification of xenobiotics. Additionally, 3,5-T 2 changes the expression of TH responsive genes, suggesting a thyromimetic action of 3,5-T 2 in mouse liver. Interestingly, 3,5-T 2 in obese but not in lean mice influences the expression of genes relevant for cholesterol and steroid biosynthesis, suggesting a novel role of 3,5-T 2 in steroid metabolism of obese mice. We concluded that treatment with 3,5-T 2 in lean and diet-induced obese male mice alters the expression of genes encoding hepatic xenobiotic-metabolizing enzymes that play a substantial role in catabolism and inactivation of xenobiotics and TH and are also involved in hepatic steroid and lipid metabolism. The administration of this high dose of 3,5-T 2 might exert adverse hepatic effects. Accordingly, the conceivable use of 3,5-T 2 as pharmacological hypolipidemic agent should be considered with caution.3,5-T 2 alters murine genes relevant for xenobiotic, steroid, and thyroid hormone metabolism

Empowering thyroid hormone research in human subjects using OMICs technologies

“…Note, that the absence of thyrotoxic side effects of 3,5-T 2 treatment could not be replicated in other animal models (Jonas et al 2015, Lietzow et al 2016. In summary, apart from secretion from the thyroid gland tissue-specific action of T 3 is achieved by specific expression patterns of the deiodinase-encoding genes (Bianco 2011).…”

3,5-T2—A Janus-Faced Thyroid Hormone Metabolite Exerts Both Canonical T3-Mimetic Endocrine and Intracrine Hepatic Action

“…3,5-T2, in contrast to its structural isomers 3,3 ′ -T2 and 3 ′ ,5 ′ -T2, is an active ligand for the classical T3 receptors (TR), where it binds with relative high affinity ( Table 4) and modulates transcriptional activity of TR, as indicated e.g., by rapid and powerful suppression of TSH in vivo, altered 3,5-T2 modulated gene expression in vitro and in several cellular models including anterior pituitary and liver (39,81,(85)(86)(87). In addition to its action on TSH suppression in thyrotropes, 3,5-T2 also stimulates growth hormone production and secretion in somatotrophs (86).…”

“…Controversial with respect to this set of observations, several other teams reported that administration of 3,5-T2 in rodent models (rat and mice, regular or high-fat diet, euthyroid or hypothyroid) dose-dependently resulted in significant suppression of the HPT axis as reflected by decreased TSH serum concentrations and/or pituitary beta-TSH transcript levels (6,39,87,94,95). Furthermore, thyromimetic effects typical for high circulating T3 were observed in the heart as analyzed by gene expression and/or morphological alterations suspicious of remodeling and fibrosis.…”

Evolution of ligands, receptors and metabolizing enzymes of thyroid signaling

“…It can induce the mRNA synthesis of several genes such as TSH (Moreno et al, 1998), Dio1 (Baur et al, 1997) or TRβ (Ball et al, 1997). More generally, in mouse, 3,5-T2 has thyromimetic activity on the hypothalamus pituitary axis and lipid metabolism (Jonas et al, 2015) as well as on the liver transcriptome (Lietzow et al, 2016). In the killifish Fundulus heteroclitus, 3,5-T2 has been shown to be a ligand for TRβ (Mendoza et al, 2013), but this idea is still debated as 3,5-T2 has a very low binding potency on TR in rat and salmon (Darling et al, 1983).…”

“…Dio2 is therefore considered as an activating deiodinase. It also turns T3 into 3,5-T2, a TH derivative long considered as inactive but for which accumulative evidences suggest a biological role (Lietzow et al, 2016;Mendoza et al, 2013). The inner ring deiodination is catalyzed by the deiodinase type III (Dio3) which is considered as an inactivating deiodinase as it turns T4 into reverse T3 (3-3'-5'-T3 or rT3) and T3 into 3-3'-T2 ( Figure 1), compounds that have no biological activity (Chopra et al, 1978;Moreno et al, 2003).…”