DEVELOPMENT AND REGULATION OF GLUCOSE-6-PHOSPHATASE GENE-EXPRESSION IN RAT-LIVER, INTESTINE, AND KIDNEY - IN-VIVO AND IN-VITRO STUDIES IN CULTURED FETAL HEPATOCYTES

The mRNA and the activity of glucose-6-phosphatase (Glc-6-Pase) mere p resent in the liver, kidney and small intestine of 15-day-old suckling rats, but were absent from the stomach, colon, lung, white and brown adipose tissues, muscle, heart, brain, and spleen. The mRNA encoding G lc-6-Pase was present in the liver of 21-day-old fetal rats and increa sed markedly immediately after birth. From 5 days after birth to the e nd of the suckling period, it returned to 50% of the level found in th e liver of 48-h starved adult rats. When rats were weaned at 21 days o nto a high-carbohydrate, low-fat (HCLF) diet, the concentration of liv er Glc-6-Pase mRNA was markedly increased. In the fetal rat jejunum, t he activity and mRNA of Glc-6-Pase mere very low It increased during t he 5 days after birth and then declined to reach very low levels. Neit her mRNA nor activity of Glc-6-Pase was present in the fetal kidney. T hey appeared and increased slowly during the suckling period to reach maximal levels 15 days after birth and then remained constant. Weaning onto the HCLF diet did not change the Glc-6-Pase gene expression, nei ther in the jejunum nor in the kidney. The regulation of Glc-6-Pase ge ne expression by hormones and nutrients was studied in cultured hepato cytes from 20-day-old rat fetuses. Bt(2)cAMP stimulated the Glc-6-Pase gene expression in a dose-dependent manner. This probably resulted fr om an increased gene transcription since the half-life of the transcri pt mas not affected by dibutyryl cAMP (Bt(2)cAMP). The Bt(2)cAMP-induc ed Glc-6-Pase mRNA accumulation was antagonized by insulin in a dose-d ependent manner. Long-chain fatty acids (LCFAs), but not medium-chain fatty acids, induced the accumulation of Glc-6-Pase mRNA and the stabi lization of the transcript. The peroxisome proliferator, clofibrate, i nduced a threefold increase in Glc-6-Pase mRNA concentration. Both sti mulation of Glc-6-Pase mRNA by LCFAs and clofibrate were inhibited by insulin. Increasing concentrations of glucose (from 0 to 20 mmol/l) di d not affect the Bt(2)cAMP-induced Glc-6-Pase gene expression By contr ast, high glucose concentration (25 mmol/l) markedly induced the Glc-6 -Pase gene expression in fed adult rat hepatocytes. The difference in the response to glucose between fetal and adult rat hepatocytes is dis cussed. We conclude that the rapid increase in hepatic Glc-6-Pase mRNA levels that accompanies the fetal-to-neonatal transition in the rat I s triggered by the reciprocal change in circulating insulin and LCFA c oncentrations, coupled to the rise in liver cAMP concentration.