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

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bile Acids and Salts / biosynthesis
  • Cytochrome P-450 Enzyme System / genetics
  • Cytochrome P-450 Enzyme System / metabolism
  • Diiodothyronines / pharmacology*
  • Energy Metabolism / drug effects*
  • Energy Metabolism / genetics*
  • Gene Expression Profiling
  • Gene Expression Regulation / drug effects*
  • Gene Expression Regulation, Enzymologic / drug effects
  • Hepatocytes / metabolism
  • Liver / metabolism
  • Male
  • Mice
  • Obesity / genetics
  • Obesity / metabolism
  • Pharmacogenetics
  • Steroids / metabolism*
  • Thyroid Hormones / metabolism*
  • Transcriptome
  • Xenobiotics / metabolism*


  • Bile Acids and Salts
  • Diiodothyronines
  • Steroids
  • Thyroid Hormones
  • Xenobiotics
  • 3,5-diiodothyronine
  • Cytochrome P-450 Enzyme System