T0901317 is a potent PXR ligand: implications for the biology ascribed to LXR

FEBS Lett. 2007 May 1;581(9):1721-6. doi: 10.1016/j.febslet.2007.03.047. Epub 2007 Mar 30.

Abstract

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.

Publication types

  • Comparative Study

MeSH terms

  • ATP-Binding Cassette Transporters / genetics
  • ATP-Binding Cassette Transporters / metabolism
  • CD36 Antigens / genetics
  • CD36 Antigens / metabolism
  • Cells, Cultured
  • Cytochrome P-450 Enzyme System / genetics
  • Cytochrome P-450 Enzyme System / metabolism
  • DNA-Binding Proteins / metabolism*
  • DNA-Binding Proteins / physiology
  • Fatty Acid Synthases / genetics
  • Fatty Acid Synthases / metabolism
  • Gene Expression Regulation / drug effects*
  • Genes, Reporter
  • Humans
  • Hydrocarbons, Fluorinated
  • Liver X Receptors
  • Luciferases / genetics
  • Luciferases / metabolism
  • Orphan Nuclear Receptors
  • Pregnane X Receptor
  • Receptors, Cytoplasmic and Nuclear / metabolism*
  • Receptors, Cytoplasmic and Nuclear / physiology
  • Receptors, Steroid / metabolism*
  • Stearoyl-CoA Desaturase / genetics
  • Stearoyl-CoA Desaturase / metabolism
  • Sterol Regulatory Element Binding Protein 1 / genetics
  • Sterol Regulatory Element Binding Protein 1 / metabolism
  • Sulfonamides / metabolism
  • Sulfonamides / pharmacology*
  • Transfection

Substances

  • ATP-Binding Cassette Transporters
  • CD36 Antigens
  • DNA-Binding Proteins
  • Hydrocarbons, Fluorinated
  • Liver X Receptors
  • NR1H3 protein, human
  • Orphan Nuclear Receptors
  • Pregnane X Receptor
  • Receptors, Cytoplasmic and Nuclear
  • Receptors, Steroid
  • Sterol Regulatory Element Binding Protein 1
  • Sulfonamides
  • TO-901317
  • Cytochrome P-450 Enzyme System
  • Luciferases
  • Stearoyl-CoA Desaturase
  • Fatty Acid Synthases