Effect of human growth hormone (GH)-binding protein in human serum on GH binding to rabbit liver membranes

Abstract

The sequence identity of growth hormone-binding protein (GH-BP) with the extracellular domain of GH receptors raised the possibility that circulating GH-BP might affect the binding of human GH (hGH) to its receptors, and thus, its biological effects. To test this hypothesis, we tested the effects of sera with low GH-BP levels (obtained from prepubertal children, girls with anorexia nervosa [AN], and patients with hepatic cirrhosis), normal control sera, and sera with high GH-BP levels (obtained from obese patients) on hGH binding to its receptors. GH-BP activity in patients' sera was measured by incubation with [ 125I]hGH and the separation of bound hGH from free hGH with dextran-coated charcoal. The effect of GH-BP was studied by preincubation of patients' sera with increasing concentrations of hGH, followed by incubation with [ 125I]hGH and a rabbit liver membrane preparation known to be rich in GH receptors, and finally by measuring hGH bound to the receptors. In this study, we report on the ability of GH-BP to reduce the inhibitory capacity (IC 50) of hGH on [ 125I]hGH binding to GH receptors. The concentration of GH-BP in serum is positively correlated with the IC 50 of hGH incubated with different sera on [ 125I]hGH binding to its receptors (n = 21; r = .886, P < .001). In the presence of high serum GH-BP levels, such as those observed in obesity ( 20.13% ± 0.71% 0.05mL serum), the IC 50 values were significantly higher than those obtained with sera containing GH-BP levels lower than those measured in human control subjects, such as from prepubertal children, AN patients, and cirrhotic patients. Based on these findings, it is proposed that increasing levels of GH-BP may modulate GH binding to its receptor, and thus may exert a negative feedback on receptor recycling and synthesis and on GH-BP cleavage from the membrane receptor or its independent expression.