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

Changes in the plasma levels of corticosteroid-binding globulin (CBG) and sex hormone-binding globulin (SHBG) from birth to adulthood sugges t that growth factors might influence clearance and/or hepatic secreti on of CBG and SHBG in humans. The effects of insulin-like growth facto r 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 cel ls, were decreased by IGF-I and insulin. However, although the CBG-to- total protein ratio was decreased dose dependently by IGF-I and insuli n, IGF-I and insulin did not dose-dependently decrease the SHBG-to-tot al protein ratio. The steady state levels of CBG and SHBG messenger RN As (mRNAs) were reduced dose dependently by IGF-I with a half-effect a t 5.4 +/- 1.9 and 4.6 +/- 1.6 nmol/L, respectively, and by insulin wit h a half-effect at 4.3 +/- 1.1 and 4.3 +/- 1.4 nmol/L, respectively. T he 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 immu noconcentration in the Hep G2 medium. In contrast, the inhibitory effe cts 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 concen trations, respectively. These results demonstrate that IGF-I reduces C BG 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 exercis es its inhibitory effects mainly on the mechanism(s) of translation an d/or excretion of CBG and SHBG. The respective effects of IGF-I and in sulin in the regulation of CBG and SHBG levels during fetal Life and p ubertal development in humans merit further study.