Fatty acid binding profile of the liver X receptor α

• Published in: Journal of lipid research 2017-02, Vol.58 (2), p.393-402
• Main Authors: Bedi, Shimpi, Hines, Genesis Victoria, Lozada-Fernandez, Valery V., de Jesus Piva, Camila, Kaliappan, Alagammai, Rider, S.Dean, Hostetler, Heather A.
• Format: Article
• Language: English
• Subjects: Acyl Coenzyme A - chemistry; Acyl Coenzyme A - metabolism; Animals; Bile acids; Chlorocebus aethiops; Cholesterol; Cholesterol - chemistry; Cholesterol - metabolism; Computer applications; Conformation; COS Cells; endogenous ligand; Excretion; Fatty Acids - chemistry; Fatty Acids - metabolism; human liver X receptor α; Humans; Hydrocarbons, Fluorinated - chemistry; Hydrocarbons, Fluorinated - metabolism; Ligands; Liver X receptors; Liver X Receptors - metabolism; long-chain fatty acid; long-chain fatty acyl-coenzyme A; medium-chain fatty acid; Oxysterols - chemistry; Oxysterols - metabolism; peroxisome proliferator-activated receptor; Protein Binding; Sulfonamides - chemistry; Sulfonamides - metabolism; transcription factor
• ISSN: 0022-2275; 1539-7262
• DOI: 10.1194/jlr.M072447

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 C10 and C12 in length.