Effect of retinoic acid on glucokinase activity and gene expression in neonatal and adult cultured hepatocytes

It has been shown that all-trans retinoic acid induces prematurely hepatic glucokinase mRNA in ten days-old neonatal rat hepatocytes, however, this ef fect could be related to the capacity of the retinoid to promote a more dif ferentiated state of the hepatocyte. In this report we demonstrate that phy siological concentrations of all-trans retinoic acid stimulate glucokinase activity in both mature fully differentiated hepatocytes and at the onset o f the induction of the enzyme in 15 to 17 days-old neonatal hepatocytes, Th e effects produced by the retinoid were similar both in magnitude and in ti me, to those elicited by insulin, a well-known stimulator of hepatic glucok inase expression, No additive effect was observed when insulin and retinoic acid were tested together, Using the branched DNA assay, a sensitive signa l amplification technique, we detected relative increases in glucokinase mR NA levels of about 70% at 3 and 24 h after the treatment with 10(-6) M all- trans retinoic acid, in both neonatal and adult hepatocytes, These data sho w that retinoic acid exerts a stimulatory effect on hepatic glucokinase ind ependent of the hepatocyte stage of maturity and suggest a physiological ro le of retinoic acid on glucose metabolism. The action of retinoic acid on h epatic glucokinase might explain previous observations on the relationship between vitamin A status and liver glycogen synthesis, These findings may s erve as basis for further investigations on the biological functions of ret inoic acid derivatives on hepatic glucose metabolism. (C) 2001 Elsevier Sci ence Inc. All rights reserved.