The Nuclear Receptor Constitutively Active/Androstane Receptor Regulates Type 1 Deiodinase and Thyroid Hormone Activity in the Regenerating Mouse Liver

Abstract

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 CARdependent manner through the up-regulation of the D1 gene.

Toxicological Assessment of Polychlorinated Biphenyls and Their Metabolites in the Liver of Baikal Seal (Pusa sibirica)

“…45,47 A recent study using mice demonstrated that CAR is involved in hepatic D1 5′-deiodinase expression and a subsequent alteration in the serum concentrations of rT 3 , which are capable of modulating T 3 target gene expression in the liver. 48 Moreover, this study suggested that liver injury such as partial hepatectomy decreases D1 5′-deiodinase activity, leading to increased rT 3 levels and the repression of T 3 target genes. 48 Another in vitro study reported that ROS inhibited DI 5′-deiodinase activity in the rabbit liver.…”

“…48 Moreover, this study suggested that liver injury such as partial hepatectomy decreases D1 5′-deiodinase activity, leading to increased rT 3 levels and the repression of T 3 target genes. 48 Another in vitro study reported that ROS inhibited DI 5′-deiodinase activity in the rabbit liver. 49 Our previous study found that CAR mRNA expression was abundant in the liver of the Baikal seal.…”

Pregnane X Receptor and Constitutive Androstane Receptor at the Crossroads of Drug Metabolism and Energy Metabolism

“…However, the net effect of CAR on TH homeostasis remains controversial. It was reported that activation of CAR decreased the serum reverse T 3 level, resulting in the desuppression of thyroid hormone target genes during partial hepatectomy (Tien et al, 2007).…”

The increased CAR-dependent metabolism of thyroid hormones in mice with high cancer susceptibility

“…Using Real-time PCR, we investigated the effects of phenobarbital on mRNA level of UDP-glucuronosyltransferase Ugt1a1, responsible for T 4 glucuronidation (Visser et al 1993), and on mRNA level of sulfotransferase Sult2a1, responsible for sulfation of thyroid hormones. We used the expression level of glyceraldehyde 3-phosphate dehydrogenase (Gapdh) as an internal control because it is known to be unaffected by phenobarbital (Tien et al 2007). As shown in Fig.…”