Rat Hepatocyte Insulin-Like Growth Factor I and Binding Protein: Effect of Growth Hormonein Vitroandin Vivo*

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Abstract
The regulation of insulin-like growth factor I (IGF I) and binding protein (BP) release by adult rat hepatocytes in primary culture were examined. Increasing the density of plating of cells had a marked positive effect on the IGF I production rate/mg cell protein, with the highest rate, .apprx. 4 pmol/mg cell protein .cntdot. 24 h, seen at densities of 1 .times. 105 cells/cm2 or higher. Cycloheximide (15 .mu.g/ml) inhibited both IGF I and BP production by more than 90%, while actinomycin D (0.1 .mu.g/ml) caused less marked, but still significant, inhibition. Over the insulin range 30 pM-300 nM there was a 45% increase in IGF I production, but no effect on BP production. Bovine GH [growth hormone] stimulated production of both peptides, significant effects (up to 50% stimulation) being seen at concentrations from 20-500 ng/ml. Cells from hypophysectomized rats, with serum IGF I and GH levels reduced more than 90% from normal, had IGF I and BP production rates only 7% of normal, measured after 48 h in culture. In vivo replacement with rat GH, 150 .mu.g/day for 5 days by osmotic minipump, significantly restored the production of both peptides by hepatocytes. Cells isolated from rats bearing the GH-secreting tumor, MtT/W15, had IGF I and BP production rates approximately twice as high as normal. A significant stimulatory effect of bovine GH (200 ng/ml) in vitro was seen on cells from normal and hypophysectomized, GH-replaced rats, but not from unreplaced hypophysectomized, or tumor-bearing rats. The results in hypophysectomized animals are consistent with known changes in hepatic GH receptors, while the lack of GH responsiveness in tumor-bearing rats indicate a persistence of maximal stimulation in culture. The reflection of in vivo GH status by hepatocytes cultured for 48 h suggests that mRNA turnover for IGF I and BP must be slow. The close parallel in the regulation of the 2 peptides under most conditions might be indicative of coordinated synthesis.