Metabolic regulation of Na+/P-i-cotransporter-1 gene expression in H4IIE cells

We showed that the rat Na+/P-i cotransporter-1 (RNaPi-1) gene was regulated by insulin and glucose in rat hepatocytes. The aim of this work was to elu cidate signaling pathways of insulin-mediated metabolic regulation of the R NaPi-1 gene in H4IIE cells. Insulin increased RNaPi-1 mRNA abundance in the presence of glucose and decreased RNaPi-1 mRNA in the absence of glucose, clearly establishing an involvement of metabolic signals for insulin-induce d upregulation of the RNaPi-1 gene. Pyruvate and insulin increased RNaPi-1 expression but downregulated L-pyruvate kinase, indicating the existence of gene-specific metabolic signals. Although fructose, glycerol, and lactate could support insulin-induced upregulation of the RNaPi-1 gene, compounds e ntering metabolism beyond pyruvate oxidation, such as acetate and citrate, could not, suggesting that RNaPi-1-specific metabolic signals are generated at or above pyruvate oxidation. Wort-mannin, LY-294002, and rapamycin abol ished the insulin effect on the RNaPi-1 gene, whereas expression of dominan t negative Asn(17) Ras and mitogen-activating protein kinase (MAPK) kinase (MEK) inhibitor PD-98059 exhibited no effect. Thus we herein propose that m etabolic regulation of RNaPi-1 expression by insulin is mediated through th e phosphatidylinositol 3-kinase/p70 ribosomal S6 kinase pathways, but not t he Ras/MAPK pathway.