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Fatty acid binding profile of the liver X receptor alpha.

Fatty acid binding profile of the liver X receptor alpha.
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Bedi S, Hines GV, Lozada-Fernandez VV, de Jesus Piva C, Kaliappan A, Rider SD, Hostetler HA,


Bedi S, Hines GV, Lozada-Fernandez VV, de Jesus Piva C, Kaliappan A, Rider SD, Hostetler HA, (click to view)

Bedi S, Hines GV, Lozada-Fernandez VV, de Jesus Piva C, Kaliappan A, Rider SD, Hostetler HA,

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Journal of lipid research 2016 12 23() pii jlr.M072447
Abstract

Liver X receptor (LXR) alpha is a nuclear receptor that responds to oxysterols and cholesterol overload by stimulating cholesterol efflux, transport, conversion to bile acids, and excretion. LXR alpha binds to and is regulated by synthetic (T-0901317, GW3695) and endogenous (oxysterols) ligands. LXR alpha activity is also modulated by fatty acids (FA) but the ligand binding specificity of FA and acyl-CoA derivatives for LXR alpha remains unknown. We investigated whether LXR alpha 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 if FA regulate LXR alpha activation. Saturated medium chain FA (MCFA) displayed binding affinities in low nanomolar concentration range, while long-chain fatty acyl CoA did not bind or bound weakly to LXR alpha. Circular dichroic spectra and computational docking experiments confirmed that MCFA bound to the LXR alpha ligand binding pocket similar to the known synthetic agonist of LXR alpha (T0901317) but with limited change to the conformation of the receptor. Transactivation assays showed MCFA activated LXR alpha, whereas LCFA caused no effect. Our results suggest that LXR alpha functions as a receptor for saturated FA or acyl-CoA of C10 and C12 in length.

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