T0901317 is a potent PXR ligand: implications for the biology ascribed to LXR.
The liver X receptors (LXRalpha and beta) are nuclear receptors that coordinate carbohydrate and lipid metabolism. Insight into the physiologic roles of the LXRs has been greatly facilitated by the discovery of potent synthetic agonists. Here we show that one of these compounds, T0901317, is also a high-affinity ligand for the xenobiotic receptor pregnane X receptor (PXR). T0901317 binds and activates PXR with the same nanomolar potency with which it stimulates LXR activity. T0901317 induces expression not only of LXR target genes, but also of PXR target genes in cells and animals, including the scavenger receptor CD36, a property not shared by more specific LXR ligands, such as GW3965. Activation of PXR targets may explain why T0901317 induces dramatic liver steatosis, while GW3965 has a milder effect. These results suggest that many of the biological activities heretofore associated with LXR activation may be mediated by PXR, not LXR. Since T0901317 has been widely used in animals to study LXR function, the in vivo effects of this compound ascribed to LXR activation should be re-examined.
Mitro
Nico
N
The Genomics Institute of the Novartis Research Foundation, San Diego, CA 92037, USA.
Vargas
Leo
L
Romeo
Russell
R
Koder
Alan
A
Saez
Enrique
E
D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D018955:CD36 Antigens / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism* / Q000502:physiology; D064429:Fatty Acid Synthases / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D017930:Genes, Reporter; D006801:Humans; D006845:Hydrocarbons, Fluorinated; D000071518:Liver X Receptors; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D057093:Orphan Nuclear Receptors; D000077297:Pregnane X Receptor; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism* / Q000502:physiology; D011987:Receptors, Steroid / Q000378:metabolism*; D013230:Stearoyl-CoA Desaturase / Q000235:genetics / Q000378:metabolism; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism; D013449:Sulfonamides / Q000378:metabolism / Q000494:pharmacology*; D014162:Transfection; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
D018528:ATP-Binding Cassette Transporters; D018955:CD36 Antigens; D003577:Cytochrome P-450 Enzyme System; D004268:DNA-Binding Proteins; D064429:Fatty Acid Synthases; D006845:Hydrocarbons, Fluorinated; D000071518:Liver X Receptors; D008156:Luciferases; D057093:Orphan Nuclear Receptors; D000077297:Pregnane X Receptor; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D013230:Stearoyl-CoA Desaturase; D051780:Sterol Regulatory Element Binding Protein 1; D013449:Sulfonamides; C000605213:NR1H3 protein, human; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides