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Tri-iodothyronine-induced increase in rat liver nuclear thyroid-hormone receptors associated with increased mitochondrial alpha-glycerophosphate dehydrogenase activity.

ABSTRACT: The effect of tri-iodothyronine injection on the nuclear tri-iodothyronine receptor (putative thyroid-hormone receptor) was examined in rat liver. Nuclear receptors were extracted from isolated nuclei with 0.4 M-KCl, and their association constants (Ka) and maximal binding capacities (Cmax.) were determined by Scatchard analyses with and without correction for the endogenous hormone. The amount of endogenous tri-iodothyronine bound to non-histone protein was estimated on the basis of the specific radio-activity of [125I]tri-iodothyronine injected 2 h before the rats were killed. It was demonstrated that Cmax. of the nuclear receptors was 2.5-fold higher in severely hyperthyroid than in hypothyroid rats. However, irrespective of the thyroid status, the Ka of the receptors remained unchanged when corrected for endogenous tri-iodothyronine bound to non-histone protein. The validity of the correction was supported by experiments in vitro in which nuclear receptors were preincubated with unlabelled tri-iodothyronine. The increase in Cmax. of nuclear receptors was directly related to mitochondrial alpha-glycerophosphate dehydrogenase activity. These results suggest a hormonal modulation of the nuclear receptors which is associated with hormonal action.

SUBMITTER: Hamada S

PROVIDER: S-EPMC1161317 | biostudies-other | 1979 Aug

REPOSITORIES: biostudies-other

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Project description:The possibility that thyroxine (T4) itself exerts the hormonal effect in vivo on the rat liver nuclear receptor was studied with the aid of iopanoic acid (IOP), an inhibitor of the conversion of T4 into tri-iodothyronine (T3). After administration of 2.4 micrograms of T4/100 g body weight to hypothyroid rats for 7 days, T4 and T3 concentrations in serum and in the liver nuclear non-histone protein (NHP) were all increased to the hyperthyroid range. Hepatic mitochondrial alpha-glycerophosphate dehydrogenase (alpha-GPD) activity and DNA content increased significantly. The equilibrium association constant (Ka) of the nuclear T3 receptor was unchanged and the maximal binding capacity (Cmax.) increased 1.4-fold. Simultaneous administration of IOP (5 mg/100 g body weight) to the rats given 2.4 micrograms of T4/100 g body weight completely blocked the conversion into T3. The serum T4 was even more increased, whereas the serum T3 decreased to the hypothyroid range. Although the NHP-bound T4 was at a concentration comparable with the rats given T4 alone, no NHP-bound T3 was detected. Yet the alpha-GPD activity was elevated 2.8-fold and the DNA content increased to the same extent as observed in the rats given T4 alone. The Ka and Cmax. of the nuclear receptor were significantly decreased. After administration of 48 or 480 micrograms of T4/100 g body weight for 3 days, serum T4 and T3 were markedly increased. The NHP-bound T3 was also increased, but no NHP-bound T4 was detected. The alpha-GPD activity was markedly elevated, but the DNA content was unchanged. The Cmax. per g of liver was increased, whereas the Ka remained unchanged. Simultaneous administration of IOP to these animals could not completely block the T4 conversion. The observed hormonal effects in the absence of nuclear T3 indicate that T4 possesses the intrinsic hormonal activities on the rat liver. T4 is less potent in induction of alpha-GPD activity but as potent in increment of hepatic DNA as T3. Although the binding site for T4 is not fully characterized, it appears to be acidic NHP. T4 is an active hormone, yet is also a prohormone of T3, offering the closest analogy with testosterone.

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Tri-iodothyronine-induced increase in rat liver nuclear thyroid-hormone receptors associated with increased mitochondrial alpha-glycerophosphate dehydrogenase activity.

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