Fatty Acids and their Thioester Derivatives as Potential Endogenous Ligands of LXRα

Abstract

The Liver X Receptor Alpha (LXRα) is a ligand‐activated nuclear transcription factor that plays a role in lipid homeostasis. Upon binding of oxysterols, LXRα is activated and regulates the transcription of target genes involved in these processes. Additionally, LXRα can form heterodimers with the Peroxisome Proliferator Activated Receptor Alpha (PPARα), another ligand‐activated nuclear receptor involved in fatty acid (FA) metabolism. Previous studies have shown that PPARα binds FAs and their thioester derivatives (FA‐CoAs); however, little is known about the effects of these ligands on the activity of LXRα. Therefore, the objective of this study was to characterize endogenous ligand binding of LXRα to FAs and FA‐CoAs. Using circular dichroism, we were able to characterize changes in the spectra of LXRα in the presence or absence of FAs and FA‐CoAs, which suggests a novel role for these nutrients in the activation of LXRα. Additionally, docking experiments were done to examine the binding affinities of these potential ligands. Our results help further elucidate the pathways by which LXRα is activated and regulates its target genes. This work was supported by USPHS NIH grant DK77573.