Luminal fructose inhibits rat intestinal sodium-phosphate cotransporter gene expression and phosphate uptake

While searching by microarray for sugar-responsive genes, we inadvertently discovered that sodium-phosphate cotransporter 2B (NaPi-2b) mRNA concentrations were much lower in fructose-perfused than in glucose-perfused intestines of neonatal rats. Changes in NaPi-2b mRNA abundance by sugars were accompanied by similar changes in NaPi-2b protein abundance and in rates of inorganic phosphate (Pi) uptake.

We tested the hypothesis that luminal fructose regulates NaPi-2b.

We perfused into the intestine fructose, glucose, and nonmetabolizable or poorly transported glucose analogs as well as phlorizin.

NaPi-2b mRNA concentrations and Pi uptake rates in fructose-perfused intestines were approximately 30% of those in glucose and its analogs. NaPi-2b inhibition by fructose is specific because the mRNA abundance and activity of the fructose transporter GLUT5 (glucose transporter 5) increased with fructose perfusion, whereas those of other transporters were independent of the perfusate. Plasma Pi after 4 h of perfusion was independent of the perfusate, probably because normal kidneys can maintain normophosphatemia. Inhibiting glucose-6-phosphatase, another fructose-responsive gene, with tungstate or vanadate nonspecifically inhibited NaPi-2b mRNA expression and Pi uptake in both glucose- or fructose-perfused intestines. The AMP kinase (AMPK)-activator AICAR (5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside) enhanced and the fatty acid synthase-AMPK inhibitor C75 (3-carboxy-4-octyl-2-methylenebutyrolactone trans-4-carboxy-5-octyl-3-methylenebutyrolactone) prevented fructose inhibition of NaPi-2b but had no effect on expression of other transporters. NaPi-2b expression decreased markedly with age and was inhibited by fructose in all age groups.

Energy levels in enterocytes may play a role in NaPi-2b inhibition by luminal fructose. Consumption of fructose that supplies approximately 10% of caloric intake by Americans clearly affects absorption of Pi and may promote Pi homeostasis in patients with impaired renal function.