Insulin antagonism of glucocorticoid induction of tyrosine aminotransferase in cultured foetal hepatocytes.
Whereas dexamethasone is unable to induce the premature formation of hepatic tyrosine aminotransferase when administered to foetal rats in utero, the steroid can induce the enzyme in foetal rat liver if the liver is first removed from the environment in utero and grown in culture. Dexamethasone produced a significant induction of the enzyme at a concentration of 0.1 nM in cultured foetal hepatocytes, but for optimal induction the cells were exposed to 10 nM for 15 h. Growing the hepatocytes in the presence of physiological concentrations of insulin had no effect on the enzyme activity in control cells. However, the induction of the enzyme by dexamethasone was markedly diminished in the presence of insulin. This effect of insulin is both time-dependent and dose-dependent with significant inhibition being obtained with 1 nM insulin. Growing foetal hepatocytes in the presence of insulin has no effect on either the cellular level of glucocorticoid receptor or on the stability of dexamethasone-receptor complexes to undergo nuclear translocation suggesting that insulin inhibits some event subsequent to translocation. The results are discussed in relation to the postnatal appearance of tyrosine aminotransferase and suggest that the marked decline in the plasma concentration of insulin, that is known to occur at birth, is a major contributor to the postnatal induction of the enzyme.
D000818:Animals; D002467:Cell Nucleus; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology*; D004336:Drug Antagonism; D004790:Enzyme Induction; D005333:Fetus; D007328:Insulin / Q000494:pharmacology*; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D051381:Rats; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D014444:Tyrosine Transaminase / Q000096:biosynthesis*
D007328:Insulin; D011965:Receptors, Glucocorticoid; D003907:Dexamethasone; D014444:Tyrosine Transaminase