GROWTH-HORMONE (GH) REGULATION OF CYTOCHROME-P-450IIC12, INSULIN-LIKE GROWTH FACTOR-I (IGF-I), AND GH RECEPTOR MESSENGER-RNA EXPRESSION IN PRIMARY RAT HEPATOCYTES - A HORMONAL INTERPLAY WITH INSULIN, IGF-I, AND THYROID-HORMONE

We have studied the GH-dependent expression of cytochrome P-450IIC12(P-450(15-beta)mRNA and insulin-like growth factor-I(IGF-I)mRNA in primary adult rat hepatocytes. The GH receptor (GHR), being the common denominator for the GH response, was also studied. The respective mRNA levels were measured with specific solution hybridization assays. By investigating the effects of insulin, IGF-1, T3, and corticosterone, alone or in combinations, in the presence or absence of GH we concluded that GH is indeed the inducer of P-450(15-beta) mRNA and IGF-I mRNA.. However, insulin and IGF-I exerted a 2-fold potentiation of the GH-induced expression of the P-450(15-beta) and IGF-1 mRNA species. No significant effect of insulin was observed on GHR mRNA expression, but a translational or posttranslational effect on GHR was seen, in that insulin increased the binding of GH to the cells 4-fold. Furthermore, T3 caused a 9-fold increase in the GH-induced expression of IGF-1 mRNA. These observations led us to postulate a possible mechanism of hormonal interplay between GH, thyroid hormone, and IGF-I in vivo, i.e. a thyroid hormone potentiation of the GH-induced IGF-I expression, which, in turn, leads to an increased GHR level and thereby a potentiation of the GH-induced expression of P-450(15-beta) and, at least transiently, of IGF-I. A transcriptional mechanism of GH action of P-450(15-beta) and IGF-I mRNA induction was indicated by the similar half-lives of respective mRNAs in the presence or absence of GH in cell cultures treated with actinomycin-D. Half-lives of 10 and 15 h were calculated for P-450(15-beta) mrna and IGF-I mRNA, respectively. An absolute requirement of on-goin protein synthesis for the induction of P-450(15-beta) mRNA by GH was evident, whereas the accumulation of IGF-i mRNA was not inhibited by cycloheximide in the same experiments. This finding could indicate more than one GH transduction mechanism. (Molecular Endocrinology 4: 1934-1942, 1990)