Dexamethasone Inversely Regulates DNA Synthesis and Phosphoenolpyruvate Carboxykinase mRNA Levels in Cultured Rat Hepatocytes: Interactions with Insulin, Glucagon, and Transforming Growth Factor β1.

Abstract

In hepatocytes, glucocorticoids control the expression of several genes and exert significant, but complex, regulation of the proliferation. To shed more light on the growth responses to glucocorticoids in these cells, we treated adult rat hepatocytes in primary culture with dexamethasone, in various combinations with other hormones (insulin, glucagon, transforming growth factor beta 1 (TGF beta 1)), and examined the relationship between the effects on the DNA synthesis and the mRNA level of phosphoenolpyruvate carboxykinase, a gene typically expressed in differentiated hepatocytes. Insulin exhibited the previously observed 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 strongly synergistically both in enhancing the phosphoenolpyruvate carboxykinase expression and inhibiting the growth, the inhibitory effect of glucagon on DNA synthesis being totally dependent on dexamethasone. The effects of dexamethasone plus glucagon on both the phosphoenolpyruvate 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 reduced the sensitivity to) TGF beta 1 on the DNA synthesis. The results indicate that there is an inverse glucocorticoid-induced regulation of the DNA synthesis and the expression of a liver-typical gene.

Isocaloric maternal low-protein diet alters IGF-I, IGFBPs, and hepatocyte proliferation in the fetal rat

“…The effect of insulin on DNA synthesis seems to be dominant by comparison with other hepatic mitogens, such as TGF-␣ and hepatocyte growth factor (22). In adult rat hepatocytes, insulin is also capable of reversing the inhibitory effect of glucagon and glucocorticoids on DNA synthesis (52).…”

“…We found that DNA synthesis was stimulated by insulin and inhibited by dexamethasone in hepatocytes isolated from control animals. Insulin has been reported to enhance DNA synthesis in both fetal and adult rat hepatocytes (27,40), but the role of glucocorticoids in hepatocyte proliferation is unclear: they have been found to potentiate DNA synthesis in the fetus (40) or inhibit it in the adult (52). The effect of insulin on DNA synthesis seems to be dominant by comparison with other hepatic mitogens, such as TGF-␣ and hepatocyte growth factor (22).…”

Change in Annexin A3 Expression by Regulatory Factors of Hepatocyte Growth in Primary Cultured Rat Hepatocytes

“…14) Other factors belong to the inhibitors group, as follows: Dex suppresses hepatocyte growth in cultured hepatocytes. [19][20][21] Hepatocytes cultured at high density show lower levels of hepatocyte growth compared with those cultured at low density. 18) Hepatocytes cultured on EHS-Matrigel 22) and PVLA 23) show extremely low levels of hepatocyte growth compared with those cultured on collagen and plastic dishes.…”

“…On the other hand, hepatocyte growth is regulated in cultured hepatocytes by various other factors including cell density, 18) humoral factors such as dexamethasone (Dex), [19][20][21] hepatocyte growth factor (HGF) and epidermal growth factor (EGF), 14) and cellular substratum such as EHS-Matrigel 22) and lactose-carrying styrene polymer (PVLA). 23) In relation to our report, the question of whether regulation of hepatocyte growth by these factors could be mediated by concurrent change in AnxA3 expression seemed interesting; however, it remained to be elucidated whether these factors cause change in AnxA3 expression.…”