The nuclear receptor constitutively active/androstane receptor regulates type 1 deiodinase and thyroid hormone activity in the regenerating mouse liver.
We observed that the level of reverse triiodothyronine (rT3) was significantly increased after partial hepatectomy (PH) in both wild-type and constitutively active/androstane receptor (CAR) knockout (KO) mice, and treatment with phenobarbital (PB), a CAR activator, after PH decreased rT3 to restore its original level only in wild-type mice. On the other hand, no significant changes in the level of total T3 or free T3 in the serum were observed in either wild-type or CAR KO mice after PH or treatment with PB. Type 1 deiodinase (D1) activity and expression were significantly reduced by PH and up-regulated by PB in a CAR-dependent manner. In addition, known T3-regulated genes [tyrosine aminotransferase (TAT) and basic transcription element binding protein (BTEB)] were also significantly decreased by PH and induced by PB. Injection of rT3 into normal mice revealed that rT3 is capable of repressing the known thyroid hormone-regulated genes Tat, Bteb, and Cpt-1 in the liver. Our results suggest that PH decreases D1 activity leading to increased rT3 level, resulting in the repression of T3 target genes. Subsequent treatment with PB decreases rT3 in a CAR-dependent manner through the up-regulation of the D1 gene.
Tien
Eric S
ES
Pharmacogenetics Section, Laboratory of Reproductive and Developmental Toxicology, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
Matsui
Kenji
K
Moore
Rick
R
Negishi
Masahiko
M
D000818:Animals; D000090702:Constitutive Androstane Receptor; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D006498:Hepatectomy; D007453:Iodide Peroxidase / Q000235:genetics*; D051741:Kruppel-Like Transcription Factors / Q000235:genetics; D008099:Liver / Q000378:metabolism*; D008115:Liver Regeneration; D051379:Mice; D008809:Mice, Inbred C3H; D018345:Mice, Knockout; D010634:Phenobarbital / Q000494:pharmacology; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology*; D014157:Transcription Factors / Q000502:physiology*; D014284:Triiodothyronine / Q000097:blood*; D014444:Tyrosine Transaminase / Q000235:genetics
D000090702:Constitutive Androstane Receptor; C489675:Klf9 protein, mouse; D051741:Kruppel-Like Transcription Factors; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D014284:Triiodothyronine; C109812:iodothyronine deiodinase type I; D007453:Iodide Peroxidase; D014444:Tyrosine Transaminase; D010634:Phenobarbital