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Large Induction of Type III Deiodinase Expression After Partial Hepatectomy in the Regenerating Mouse and Rat Liver

Department of Internal Medicine (M.H.A.K., A.M.A., T.J.V.), Erasmus Medical Center, 3015 GE Rotterdam, The Netherlands; Department of Pathobiology (M.J.M.T., C.A.P., R.M., M.E.E., A.d.B.), Utrecht University, 3512 BS Utrecht, The Netherlands; and Laboratory of Comparative Endocrinology (V.M.D.), Catholic University Leuven, 3000 Leuven, Belgium

Address all correspondence and requests for reprints to: Theo J. Visser, Department of Internal Medicine, Erasmus Medical Center, Room Ee 502, Dr Molewaterplein 50, 3015 GE Rotterdam, The Netherlands. E-mail: t.j.visser{at}erasmusmc.nl.

The deiodinase types 1 (D1) and 2 (D2) catalyze the activation of T₄ to T₃, whereas type 3 deiodinase (D3) catalyzes the inactivation of T₃ and T₄. D3 plays a key role in controlling thyroid hormone bioavailability. It is highly expressed during fetal development, but also in other processes with increased cell proliferation, e.g. in vascular tumors. Because tissue regeneration is dependent on cellular proliferation and is associated with activation of fetal genes, we evaluated deiodinase activities and mRNA expression in rat and mouse liver, as well as the local and systemic thyroid hormone status after partial hepatectomy (PH). We observed that in rats, D3 activity was increased 10-fold at 20 h and 3-fold at 48 h after PH; D3 mRNA expression was increased 3-fold at 20 h. The increase in D3 expression was associated with maximum 2- to 3-fold decreases of serum and liver T₃ and T₄ levels at 20 to 24 h after PH. In mice, D3 activity was increased 5-fold at 12 h, 8-fold at 24 h, 40-fold at 36 h, 15-fold at 48 h, and 7-fold at 72 h after PH. In correlation with this, D3 mRNA was highest (6-fold increase), and serum T₃ and T₄ were lowest at 36 h. Furthermore, as a measure for cell proliferation, 5-bromo-2'-deoxyuridine incorporation peaked at 20–24 h after PH in rats and at 36 h in mice. No significant effect on D1 activity or mRNA expression was found after PH. D2 activity was always undetectable. In conclusion, we found a large induction of hepatic D3 expression after PH that was correlated with an increased cellular proliferation and decreased serum and liver T₃ and T₄ levels. Our data suggest that D3 is important in the modulation of thyroid hormone levels in the regenerating liver, in which a decrease in cellular T₃ permits an increase in proliferation.

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