EFFECT OF 3,5,3'-TRIIODOTHYRONINE (T-3) ADMINISTRATION ON DIO1 GENE-EXPRESSION AND T-3 METABOLISM IN NORMAL AND TYPE-1 DEIODINASE-DEFICIENT MICE

The type 1 deiodinase (D1) catalyzes the monodeiodination of T-4 to produce T-3, the active thyroid hormone. In the C3H mouse, hepatic D1 and the dio1 messenger RNA (mRNA) are only 10% that in the C57 strain, the common phenotype. Low activity cosegregated with a series of five GCT repeats located in the 5'-flanking region of the C3H dio1 gene that impaired C3H promoter potency and provided a partial explanation for the lower D1. The present studies were performed to search for additional explanations for low D1 activity in C3H mice. Previous studies have shown that T-3 up-regulates the diol gene. Therefore, loss of the capacity to respond to endogenous T-3 is a possible additional cause of the lower D1 levels in the C3H mice. The hepatic C3H dio1 mRNA increases 10- to 20-fold after T-3 administration. The T-3 effect occurs at a transcriptional level and T-3 does not alter the diol mRNA half-life. Despite the transcriptional response to T-3, no functional thyroid response elements were identified in the 1.5-kilobase 5'-flanking region of either the C57 or C3H dio1 gene. After the same dose of exogenous T-3, both dio1 mRNA and D1 of the C3H mouse respond to a greater extent than those of the C57 strain. This can be explained in part by the reduction in T-3 clearance due to the lower D1 levels in C3H mice in which higher concentrations of circulating T-3 are maintained. The decrease in serum T-3 levels and T-3 production observed in fasting and systemic illness in both human and experimental animals has been attributed in part to a decrease in hepatic D1. In contrast, despite markedly lower hepatic and renal D1 levels, serum T-3 concentrations remain normal in C3H mice. The present studies suggest that the absence of stress-induced hypothalamic-pituitary suppression that allows T-4 production to be maintained together with the reduced clearance of T-3 and T-4 via inner ring deiodination compensate for the D1 deficiency.