title: 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-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.
authors.affiliation: Institut für Experimentelle EndokrinologieCharité - Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Julika
authors.initials: J
authors.lastname: Lietzow
authors.affiliation: Interfaculty Institute for Genetics and Functional GenomicsDepartment of Functional Genomics, University Medicine Greifswald, Greifswald, Germany.
authors.forename: Janine
authors.initials: J
authors.lastname: Golchert
authors.affiliation: Interfaculty Institute for Genetics and Functional GenomicsDepartment of Functional Genomics, University Medicine Greifswald, Greifswald, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Homuth
authors.affiliation: Interfaculty Institute for Genetics and Functional GenomicsDepartment of Functional Genomics, University Medicine Greifswald, Greifswald, Germany.
authors.forename: Uwe
authors.initials: U
authors.lastname: Völker
authors.affiliation: Department of Experimental DiabetologyGerman Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany German Center for Diabetes Research (DZD)Helmholtz Center Munich, Neuherberg, Germany.
authors.forename: Wenke
authors.initials: W
authors.lastname: Jonas
authors.affiliation: Institut für Experimentelle EndokrinologieCharité - Universitätsmedizin Berlin, Berlin, Germany josef.koehrle@charite.de.
authors.forename: Josef
authors.initials: J
authors.lastname: Köhrle
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000096:biosynthesis; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D004104:Diiodothyronines / Q000494:pharmacology*; D004734:Energy Metabolism / Q000187:drug effects* / Q000235:genetics*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D022781:Hepatocytes / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D009765:Obesity / Q000235:genetics / Q000378:metabolism; D010597:Pharmacogenetics; D013256:Steroids / Q000378:metabolism*; D013963:Thyroid Hormones / Q000378:metabolism*; D059467:Transcriptome; D015262:Xenobiotics / Q000378:metabolism*
chemical_list: D001647:Bile Acids and Salts; D004104:Diiodothyronines; D013256:Steroids; D013963:Thyroid Hormones; D015262:Xenobiotics; C030103:3,5-diiodothyronine; D003577:Cytochrome P-450 Enzyme System
keywords: 3,5-diiodo-l-thyronine (3,5-T2); cholesterol metabolism; constitutive androstane receptor (CAR); drug metabolism; steroid metabolism; thyroid hormone; transcriptome analysis