DEXAMETHASONE INVERSELY REGULATES DNA-SYNTHESIS AND PHOSPHOENOLPYRUVATE CARBOXYKINASE MESSENGER-RNA LEVELS IN CULTURED RAT HEPATOCYTES - INTERACTIONS WITH INSULIN, GLUCAGON, AND TRANSFORMING GROWTH-FACTOR-BETA-1

In hepatocytes, glucocorticoids control the expression of several gene s and exert significant, but complex, regulation of the proliferation. To shed more light on the growth responses to glucocorticoids in thes e cells, we treated adult rat hepatocytes in primary culture with dexa methasone, in Various combinations with other hormones (insulin, gluca gon, transforming growth factor beta 1 (TGF beta 1)), and examined the relationship between the effects on the DNA synthesis and the mRNA le vel of phosphoenolpyruvate carboxykinase, a gene typically expressed i n differentiated hepatocytes. Insulin exhibited the previously observe d suppressing effect on the glucocorticoid-induced phosphoenolpyruvate carboxykinase mRNA level, and also reversed growth-inhibitory effects of the glucocorticoid. Dexamethasone and glucagon (via cAMP) acted st rongly synergistically both in enhancing the phosphoenolpyruvate carbo xykinase expression and inhibiting the growth, the inhibitory effect o f glucagon on DNA synthesis being totally dependent on dexamethasone. The effects of dexamethasone plus glucagon on both the phosphoenolpyru vate carboxykinase mRNA abundance and the DNA synthesis were partially counteracted by insulin. Dexamethasone is permissive for a promoting effect of TGF beta 1 on phosphoenolpyruvate carboxykinase expression, and was found to increase the maximal inhibitory effect of (but reduce d the sensitivity to) TGF beta 1 on the DNA synthesis. The results ind icate that there is an inverse glucocorticoid-induced regulation of th e DNA synthesis and the expression of a liver-typical gene.