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J Mol Endocrinol. 2016 May;56(4):311-23. doi: 10.1530/JME-15-0159. Epub 2016 Feb 22.

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

Author information

1
Institut für Experimentelle EndokrinologieCharité - Universitätsmedizin Berlin, Berlin, Germany.
2
Interfaculty Institute for Genetics and Functional GenomicsDepartment of Functional Genomics, University Medicine Greifswald, Greifswald, Germany.
3
Department of Experimental DiabetologyGerman Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany German Center for Diabetes Research (DZD)Helmholtz Center Munich, Neuherberg, Germany.
4
Institut für Experimentelle EndokrinologieCharité - Universitätsmedizin Berlin, Berlin, Germany josef.koehrle@charite.de.

Abstract

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.

KEYWORDS:

3,5-diiodo-l-thyronine (3,5-T2); cholesterol metabolism; constitutive androstane receptor (CAR); drug metabolism; steroid metabolism; thyroid hormone; transcriptome analysis

PMID:
26903510
DOI:
10.1530/JME-15-0159
[Indexed for MEDLINE]

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