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 effect could be related to the capacity of the retinoid to promote a more differentiated state of the hepatocyte. In this report we demonstrate that physiological concentrations of all-trans retinoic acid stimulate glucokinase activity in both mature fully differentiated hepatocytes and at the onset of the induction of the enzyme in 15 to 17 days-old neonatal hepatocytes. The effects produced by the retinoid were similar both in magnitude and in time, to those elicited by insulin, a well-known stimulator of hepatic glucokinase expression. No additive effect was observed when insulin and retinoic acid were tested together. Using the branched DNA assay, a sensitive signal amplification technique, we detected relative increases in glucokinase mRNA 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 show that retinoic acid exerts a stimulatory effect on hepatic glucokinase independent of the hepatocyte stage of maturity and suggest a physiological role of retinoic acid on glucose metabolism. The action of retinoic acid on hepatic glucokinase might explain previous observations on the relationship between vitamin A status and liver glycogen synthesis. These findings may serve as basis for further investigations on the biological functions of retinoic acid derivatives on hepatic glucose metabolism.
Cabrera-Valladares
G
G
Unidad de Genetica de la Nutricion, Instituto de Investigaciones Biomedicas, Universidad Nacional Autonoma de Mexico/Instituto Nacional de Pediatria, Mexico City.
Matschinsky
F M
FM
Wang
J
J
Fernandez-Mejia
C
C
D000818:Animals; D000831:Animals, Newborn; D000833:Animals, Suckling; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004790:Enzyme Induction / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects*; D005941:Glucokinase / Q000096:biosynthesis* / Q000235:genetics; D022781:Hepatocytes / Q000187:drug effects* / Q000201:enzymology*; D007328:Insulin / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D014212:Tretinoin / Q000494:pharmacology*
D007328:Insulin; D012333:RNA, Messenger; D014212:Tretinoin; D005941:Glucokinase