A Natural Product Ligand of the Oxysterol Receptor, Liver X Receptor

Abstract

Natural products have been identified as ligands for a number of members of the nuclear hormone receptor (NHR) superfamily. Often these natural products are used as dietary supplements to treat myriad ailments ranging from perimenopausal hot flashes to hypercholesterolemia and reduced cognitive function. Examples of some natural product ligands for NHRs include genestein (estrogen receptors NR3A1 and NR3A2), guggulsterone (farnesoid X receptor NR1H4), and St. John's wort (pregnane X receptor, NR1I2). In this study, we identified the first nonoxysterol natural product that functions as a ligand for the liver X receptor (LXR␣ and LXR␤; NR1H3, NR1H2), a NHR that acts as the receptor for oxysterols and plays a key role in regulation of cholesterol metabolism and transport as well as glucose metabolism. We show that paxilline, a fungal metabolite, is an efficacious agonist of both LXR␣ and LXR␤ in biochemical and in vitro cell-based assays. Paxilline binds directly to both receptors and is an activator of LXR-dependent transcription in cell-based reporter assays. We also demonstrate that paxilline binding to the receptors results in efficient activation of transcription of two physiological LXR target genes, ABCA1 and SREBP. The discovery of paxilline, the first reported nonoxysterol natural product ligand of the LXRs, may provide insight into the mechanism of ligand recognition by these receptors and reaffirms the utility of examining natural product libraries for identifying novel NHR ligands.

Ligand specificity and evolution of liver X receptors

“…Krasowski, unpublished data). We also found that paxilline, a fungal metabolite reported to activate LXRα and LXRβ [30], also activated zebrafish, Xenopus laevis, and Xenopus tropicalis LXRs, although with much lower efficacy than T-0901317 (Tables 1 and 2). …”

Liver X receptors contribute to the protective immune response against Mycobacterium tuberculosis in mice

“…Distinct pathogen-specific molecules acting as pathogen-associated molecular patterns and/or as LXR ligands likely cause the divergent outcomes of LXR activation in these infection models. A report that the fungal metabolite paxilline is a potent LXR agonist supports this proposition (50). In addition, M. tuberculosis contains an array of unique lipid components in its outer cell envelope that could act as potential LXR ligands.…”

The Hypolipidemic Natural Product Guggulsterone Is a Promiscuous Steroid Receptor Ligand

“…Radioligand binding assays were performed using either the charcoal separation or scintillation proximity technology as described previously (Palmer et al, 2000;Bramlett et al, 2003). Tritiated radioligands were used for all assays with the exception of thyroid hormone receptor (TR) and included dexamethasone (GR), methyltrienolone (R1881) (AR), aldosterone (MR), promegestone (R5020) (PR), GW4064 (FXR), T1317 (liver X receptor ␣, LXR␣), 9-cis retinoic acid, 17␤-estradiol (ER), peroxisome proliferator-activated receptor (PPAR) ␣ and PPAR␦ (LY427697), and PPAR␥ (LY509547) (Brooks et al, 2001;Xu et al, 2004).…”