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

    1. Josef Köhrle1
    1. 1Institut für Experimentelle Endokrinologie, Charité – Universitätsmedizin Berlin, Berlin, Germany
    2. 2Interfaculty Institute for Genetics and Functional Genomics, Department of Functional Genomics, University Medicine Greifswald, Greifswald, Germany
    3. 3Department of Experimental Diabetology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany
    4. 4German Center for Diabetes Research (DZD), Helmholtz Center Munich, Neuherberg, Germany
    1. Correspondence should be addressed to J Köhrle; Email: josef.koehrle{at}charite.de


    The endogenous thyroid hormone (TH) metabolite 3,5-diiodo-l-thyronine (3,5-T2) 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-T2 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-T2 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-T2. Our results revealed that 3,5-T2 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-T2 changes the expression of TH responsive genes, suggesting a thyromimetic action of 3,5-T2 in mouse liver. Interestingly, 3,5-T2 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-T2 in steroid metabolism of obese mice. We concluded that treatment with 3,5-T2 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-T2 might exert adverse hepatic effects. Accordingly, the conceivable use of 3,5-T2 as pharmacological hypolipidemic agent should be considered with caution.

    • Received 13 February 2016
    • Accepted 22 February 2016
    • Made available online as an Accepted Preprint 1 May 2016
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