Fatty acid binding profile of the liver X receptor α.
Publication/Presentation Date
2-1-2017
Abstract
Liver X receptor (LXR)α is a nuclear receptor that responds to oxysterols and cholesterol overload by stimulating cholesterol efflux, transport, conversion to bile acids, and excretion. LXRα binds to and is regulated by synthetic (T-0901317, GW3695) and endogenous (oxysterols) ligands. LXRα activity is also modulated by FAs, but the ligand binding specificity of FA and acyl-CoA derivatives for LXRα remains unknown. We investigated whether LXRα binds FA or FA acyl-CoA with affinities that mimic in vivo concentrations, examined the effect of FA chain length and the degree of unsaturation on binding, and investigated whether FAs regulate LXRα activation. Saturated medium-chain FA (MCFA) displayed binding affinities in the low nanomolar concentration range, while long-chain fatty acyl-CoA did not bind or bound weakly to LXRα. Circular dichroic spectra and computational docking experiments confirmed that MCFA bound to the LXRα ligand binding pocket similar to the known synthetic agonist of LXRα (T0901317), but with limited change to the conformation of the receptor. Transactivation assays showed that MCFA activated LXRα, whereas long-chain FA caused no effect. Our results suggest that LXRα functions as a receptor for saturated FA or acyl-CoA of C
Volume
58
Issue
2
First Page
393
Last Page
402
ISSN
1539-7262
Published In/Presented At
Bedi, S., Hines, G. V., Lozada-Fernandez, V. V., de Jesus Piva, C., Kaliappan, A., Rider, S. D., Jr, & Hostetler, H. A. (2017). Fatty acid binding profile of the liver X receptor α. Journal of lipid research, 58(2), 393–402. https://doi.org/10.1194/jlr.M072447
Disciplines
Medicine and Health Sciences
PubMedID
28011707
Department(s)
Fellows and Residents
Document Type
Article