title: Liver X receptor-activating ligands modulate renal and intestinal sodium-phosphate transporters.
abstract: Cholesterol is pumped out of the cells in different tissues, including the vasculature, intestine, liver, and kidney, by the ATP-binding cassette transporters. Ligands that activate the liver X receptor (LXR) modulate this efflux. Here we determined the effects of LXR agonists on the regulation of phosphate transporters. Phosphate homeostasis is regulated by the coordinated action of the intestinal and renal sodium-phosphate (NaPi) transporters, and the loss of this regulation causes hyperphosphatemia. Mice treated with DMHCA or TO901317, two LXR agonists that prevent atherosclerosis in ApoE or LDLR knockout mice, significantly decreased the activity of intestinal and kidney proximal tubular brush border membrane sodium gradient-dependent phosphate uptake, decreased serum phosphate, and increased urine phosphate excretion. The effects of DMHCA were due to a significant decrease in the abundance of the intestinal and renal NaPi transport proteins. The same effect was also found in opossum kidney cells in culture after treatment with either agonist. There was increased nuclear expression of the endogenous LXR receptor, a reduction in NaPi4 protein abundance (the main type II NaPi transporter in the opossum cells), and a reduction in NaPi co-transport activity. Thus, LXR agonists modulate intestinal and renal NaPi transporters and, in turn, serum phosphate levels.
authors.affiliation: Department of Medicine, Division of Renal Diseases and Hypertension, University of Colorado Denver, Aurora, Colorado 80045, USA.
authors.forename: Yupanqui A
authors.initials: YA
authors.lastname: Caldas
authors.forename: Hector
authors.initials: H
authors.lastname: Giral
authors.forename: Michael A
authors.initials: MA
authors.lastname: Cortázar
authors.forename: Eileen
authors.initials: E
authors.lastname: Sutherland
authors.forename: Kayo
authors.initials: K
authors.lastname: Okamura
authors.forename: Judith
authors.initials: J
authors.lastname: Blaine
authors.forename: Victor
authors.initials: V
authors.lastname: Sorribas
authors.forename: Hermann
authors.initials: H
authors.lastname: Koepsell
authors.forename: Moshe
authors.initials: M
authors.lastname: Levi
mesh_terms: D000818:Animals; D001692:Biological Transport; D006706:Homeostasis; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D007668:Kidney / Q000378:metabolism; D008024:Ligands; D000071518:Liver X Receptors; D051379:Mice; D057093:Orphan Nuclear Receptors / Q000819:agonists / Q000378:metabolism*; D010710:Phosphates / Q000378:metabolism / Q000652:urine; D050608:Sodium-Phosphate Cotransporter Proteins / Q000378:metabolism*
chemical_list: D008024:Ligands; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D010710:Phosphates; D050608:Sodium-Phosphate Cotransporter Proteins