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 elucidate signaling pathways of insulin-mediated metabolic regulation of the RNaPi-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-induced 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 entering 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. Wortmannin, LY-294002, and rapamycin abolished the insulin effect on the RNaPi-1 gene, whereas expression of dominant negative Asn(17) Ras and mitogen-activating protein kinase (MAPK) kinase (MEK) inhibitor PD-98059 exhibited no effect. Thus we herein propose that metabolic regulation of RNaPi-1 expression by insulin is mediated through the phosphatidylinositol 3-kinase/p70 ribosomal S6 kinase pathways, but not the Ras/MAPK pathway.
Xie
Z
Z
Department of Pharmacology, Medical College of Ohio, Toledo, Ohio 43614-5804, USA. zxie@mco.edu
Li
H
H
Liu
L
L
Kahn
B B
BB
Najjar
S M
SM
Shah
W
W
D000256:Adenoviridae / Q000235:genetics; D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D015152:Blotting, Northern; D002352:Carrier Proteins / Q000096:biosynthesis* / Q000235:genetics*; D002460:Cell Line; D002467:Cell Nucleus / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000235:genetics* / Q000502:physiology*; D005947:Glucose / Q000494:pharmacology; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000494:pharmacology; D008114:Liver Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D019289:Pyruvic Acid / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D015398:Signal Transduction / Q000502:physiology; D020123:Sirolimus / Q000494:pharmacology; D050608:Sodium-Phosphate Cotransporter Proteins; D027981:Symporters; D014158:Transcription, Genetic / Q000235:genetics; D000077191:Wortmannin
D000730:Androstadienes; D000903:Antibiotics, Antineoplastic; D002352:Carrier Proteins; D004791:Enzyme Inhibitors; D007004:Hypoglycemic Agents; D007328:Insulin; D012333:RNA, Messenger; D050608:Sodium-Phosphate Cotransporter Proteins; D027981:Symporters; D019289:Pyruvic Acid; D019950:Mitogen-Activated Protein Kinase 1; D005947:Glucose; D020123:Sirolimus; D000077191:Wortmannin