Epidermal growth factor stimulates glycogen synthesis in fetal rat hepatocytes: comparison with the glycogenic effects of insulin-like growth factor I and insulin.
The effects of epidermal growth factor (EGF) on glycogen metabolism and the binding of [125I]iodo-EGF to receptors in fetal rat hepatocytes have been examined. The actions of EGF have been compared with those of insulin-like growth factor I (IGF-I) and insulin. EGF (0.1-45 nM) stimulated dose-dependent increases in [14C]glucose incorporation into glycogen (8.8-31.1%, P less than 0.01) and total cellular glycogen content (5.6-21.4%, P less than 0.05). The concentration of EGF causing half-maximal stimulation of glycogen synthesis was 2 ng/ml, and maximal stimulation occurred at 1 h of incubation. EGF had no effect on the uptake of the nonmetabolizable monosaccharide [14C]O-methyl-D-glucose, suggesting that the glycogenic effect of EGF was not mediated through stimulation of glucose transport. Although IGF-I (1-100 nM) and insulin (14 nM to 10 microM) also stimulated glycogen synthesis in fetal liver, the maximal effects of these hormones occurred at 2 h incubation, and the dose-response curves of IGF-I and insulin were not parallel to that of EGF. In addition, the maximal glycogenic effect of EGF was only 40% that of insulin or IGF-I, and the effects of EGF and insulin on [14C]glucose incorporation were additive. These findings suggest that EGF stimulates glycogen synthesis through a mechanism distinct from that of IGF-I or insulin. The binding of [125I]iodo-EGF to fetal hepatocytes was specific, saturable, and time- and temperature-dependent. Maximal specific binding occurred at 1 h of incubation at 37 C or at 24 h of incubation at 4 C. Unlabeled EGF (0.05-250 ng/ml) caused a dose-dependent inhibition of the binding of [125I]iodo-EGF to fetal hepatocytes, with half-maximal displacement of [125I]iodo-EGF by 1.7 ng unlabeled EGF/ml. The specific binding of [125I] iodo-EGF was not inhibited by high concentrations of insulin or IGF-I, suggesting that the differences in the mechanisms by which EGF, insulin, and IGF-I stimulate glycogenesis may be explained in part by differences in the binding of these hormones to fetal liver receptors. In addition to having mitogenic effects in fetal tissue, EGF or other EGF-like growth factors may have acute effects on fetal hepatic intermediary metabolism and may contribute to the accumulation of liver glycogen in the mammalian fetus during late gestation.
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