Fatty acid binding profile of the liver X receptor α

Liver X receptor (LXR) is a nuclear receptor that responds to oxysterols and cholesterol overload by stimulating cholesterol efflux, transport, conversion to bile acids, and excretion. LXR binds to and is regulated by synthetic (T-0901317, GW3695) and endogenous (oxysterols) ligands. LXR activity is also modulated by FAs, but the ligand binding specificity of FA and acyl-CoA derivatives for LXR remains unknown. We investigated whether LXR 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 LXR 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 LXR. Circular dichroic spectra and computational docking experiments confirmed that MCFA bound to the LXR ligand binding pocket similar to the known synthetic agonist of LXR (T0901317), but with limited change to the conformation of the receptor. Transactivation assays showed that MCFA activated LXR, whereas long-chain FA caused no effect. Our results suggest that LXR functions as a receptor for saturated FA or acyl-CoA of C-10 and C-12 in length.