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

The type 1 deiodinase (D1) catalyzes the monodeiodination of T-4 to pr oduce T-3, the active thyroid hormone. In the C3H mouse, hepatic D1 an d the dio1 messenger RNA (mRNA) are only 10% that in the C57 strain, t he common phenotype. Low activity cosegregated with a series of five G CT 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 additio nal explanations for low D1 activity in C3H mice. Previous studies hav e shown that T-3 up-regulates the diol gene. Therefore, loss of the ca pacity 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 increas es 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 re sponse 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 exten t than those of the C57 strain. This can be explained in part by the r eduction in T-3 clearance due to the lower D1 levels in C3H mice in wh ich higher concentrations of circulating T-3 are maintained. The decre ase in serum T-3 levels and T-3 production observed in fasting and sys temic illness in both human and experimental animals has been attribut ed in part to a decrease in hepatic D1. In contrast, despite markedly lower hepatic and renal D1 levels, serum T-3 concentrations remain nor mal in C3H mice. The present studies suggest that the absence of stres s-induced hypothalamic-pituitary suppression that allows T-4 productio n to be maintained together with the reduced clearance of T-3 and T-4 via inner ring deiodination compensate for the D1 deficiency.