Previous evidence suggests the existence of a thyroid hormone-IGF axis in the liver and changes in hepatic insulin-like growth factor binding protein (IGFBP) expression in rats with altered thyroid status have been previously reported. The aim of this study was to check if the higher IGFBP-2 mRNA levels observed in liver of hypothyroid rats could be due to a direct effect of thyroid hormone on the IGFBP-2 gene. In our experiments, cultured hepatocytes isolated from normal and hypothyroid adult rats were used. Northern blot analysis revealed barely detectable IGFBP-2 mRNA in normal rat hepatocytes, but easily detectable signal in hypothyroid rat cells. Therefore, the effect of tri-iodothyronine (T3) was investigated using cultured hepatocytes from hypothyroid rats as an in vitro model. The IGFBP-2 message was increased in a dose-dependent manner in hepatocytes cultured for 12-24 h in the presence of T3. A similar increase occurred in accumulation of IGFBP-2 in the culture medium, as measured by RIA. The effect of T3 on IGFBP-2 transcript levels appeared to consist of enhanced gene transcription and was independent of ongoing protein synthesis, but it was completely abolished by the incubation of hepatocytes with insulin. The latter result confirmed the dominant role of insulin in regulating IGFBP-2 expression by cultured hepatocytes. In vivo experiments confirmed an increase in hepatic IGFBP-2 mRNA and serum IGFBP-2 levels in hypothyroid rats and demonstrated, in addition, a significant increase in these measures in T3-treated rats. Taken together, our in vitro and in vivo results support a role for a thyroid hormone-IGF axis in the liver and suggest that other factors, such as insulin, interact in vivo with thryoid hormone in regulating hepatic IGFBP-2 expression.

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