Role of the Liver in Regulating Somatomedin Activity: Hormonal Effects on the Synthesis and Release of Insulin-Like Growth Factor and Its Carrier Protein by the Isolated Perfused Rat Liver*

Previous studies have indicated that one or more GH-dependen t somatomedins (SMs) are either synthesized or at least released by the liver. Employing the isolated rat liver perfusion technique and a competitive protein-binding assay to measure one of the SMs insulin-like growth factor (IGF) and its carrier protein (CP), the net cumulative release of these peptides from normal and hypophysectomized (hypox) rat livers has been studied. The IGF concentration in the perfusates of seven normal livers increased rapidly during the initial 2 h and more gradually during the remainder of a 12-h perfusion. The mean (± SEM) net cumulative release of IGF at 12 h was 5620 ± 740 μU/300 cm2 (donor body surface area). In contrast to the pattern of IGF release, the release of CP was very slow initially but increased rapidly by the 12th h to 5.0 ± 0.9 mg/300 cm2. The addition of bovine GH to the perfusions of six normal livers caused a significant increase in the release of IGF(9210 ± 850 μU/300 cm2) but not of CP (5.4 ± 0.9 mg/300 cm2). The augmented release of IGF was significantly reduced by the addition of puromycin to the GH-supplemented perfusion of three normal livers (3798 ± 1142 μU/300 cm2), suggesting that IGF released under GH-stimulated conditions consists of both stored and newly synthesized peptide. The release of CP from GH-treated livers exposed to puromycin (3.1 ± 0.5 mg/300 cm2) was slightly but not significantly decreased relative to control and GH-stimulated normal livers. Ovine PRL stimulated a small but possibly significant increase in IGF release but did not alter the release of CP. Porcine insulin, even in supraphysiological doses, had no effect on either IGF or CP release. Hypophysectomy of donor rats produced a dramatic fall in both IGF and CP release. Virtually no IGF and very little CP were released from seven hypox rat livers in the presence of partial hormone supplementation (GH, T3, cortisol, or insulin). Full hormone supplementation (all four hormones) added to the perfusions of four hypox rat livers stimulated some IGF release (741 ± 306 μU/300 cm2), though it was significantly less than that of normal livers. Similarly, CP release was significantly increased to 2.2 ± 0.2 mg/300 cm2. Pretreatment of three donor hypox rats with bovine GH, T3) and cortisol for 3 days before sacrifice further increased IGF release (2720 ± 250 μU/300 cm2) but did not restore it to normal. Such hormone replacement therapy did not further augment the release of CP. Confirmatory evidence for the hormonal regulation of IGF and CP synthesis and release has been derived from measuring IGF and CP levels in the sera of hypox rats receiving partial or full hormone replacement therapy. Only when GH, T3, and cortisol were administered together did the serum concentration of IGF reach normal and that of CP approach 50% of the control value. These data suggest that GH may occupy a central role in regulating the hepatic synthesis or release of IGF and CP, but that both T3 and cortisol are necessary to restore these functions to normal in hypox rats.