Differential effects of insulin and insulin-like growth factor I on the production of plasma steroid-binding globulins by human hepatoblastoma-derived (Hep G2) cells

Abstract

Changes in the plasma levels of corticosteroid-binding globulin (CBG) and sex hormone-binding globulin (SHBG) from birth to adulthood suggest that growth factors might influence clearance and/or hepatic secretion of CBG and SHBG in humans. The effects of insulin-like growth factor I (IGF-I) and insulin on CBG and SHBG synthesis by a clone of human hepatoblastoma-derived (Hep G2) cell lines were therefore investigated. The results showed that the immunoconcentrations of CBG and SHBG, as well as total protein concentration in culture medium from Hep G2 cells, were decreased by IGF-I and insulin. However, although the CBG-to-total protein ratio was decreased dose dependently by IGF-I and insulin, IGF-I and insulin did not dose-dependently decrease the SHBG-to-total protein ratio. The steady state levels of CBG and SHBG messenger RNAs (mRNAs) were reduced dose dependently by IGF-I with a half-effect at 5.4 +/- 1.9 and 4.6 +/- 1.6 nmol/L, respectively, and by insulin with a half-effect at 4.3 +/- 1.1 and 4.3 +/- 1.4 nmol/L, respectively. The maximum inhibitory effect of IGF-I on CBG mRNA level was 48 +/- 17% of control values and 60 +/- 13% for SHBG mRNA level. The changes in CBG mRNA levels were quantitatively similar to the changes in CBG immunoconcentration in the Hep G2 medium. In contrast, the inhibitory effects of insulin were only 17 +/- 8% and 31 +/- 12% of control values on CBG and SHBG mRNAs and 37 +/- 4% and 43 +/- 4% on CBG and SHBG concentrations, respectively. These results demonstrate that IGF-I reduces CBG and SHBG production by Hep G2 cells by decreasing mRNA steady state levels. The discrepancy between the inhibitory effects of insulin on CBG and SHBG mRNAs and protein secretion suggests that insulin exercises its inhibitory effects mainly on the mechanism(s) of translation and/or excretion of CBG and SHBG. The respective effects of IGF-I and insulin in the regulation of CBG and SHBG levels during fetal life and pubertal development in humans merit further study.