Open the LID: LXRα regulates ChREBPα transactivity in a target gene-specific manner through an agonist-modulated LBD-LID interaction

The cholesterol-sensing nuclear receptor liver X receptor (LXR) and the glucose-sensing transcription factor carbohydrate responsive element-binding protein (ChREBP) are central players in regulating glucose and lipid metabolism in liver. We have previously shown that LXR regulates ChREBP transcription and activity; however, the underlying mechanisms are unclear. In the current study, we demonstrate that LXR and ChREBP interact physically, and show a high co-occupancy at regulatory regions in the mouse genome. LXR co-activates ChREBP, and regulates ChREBP-specific target genes in vitro and in vivo. This co-activation is dependent on functional recognition elements for ChREBP, but not for LXR, indicating that ChREBP recruits LXR to chromatin in trans. The two factors interact via their key activation domains; ChREBPs low glucose inhibitory domain (LID) and the ligand-binding domain (LBD) of LXR. While unliganded LXR co-activates ChREBP, ligand-bound LXR surprisingly represses ChREBP activity on ChREBP-specific target genes. Mechanistically, this is due to a destabilized LXR:ChREBP interaction, leading to reduced ChREBP-binding to chromatin and restricted activation of glycolytic and lipogenic target genes. This ligand-driven molecular switch highlights an unappreciated role of LXR that was overlooked due to LXR lipogenesis-promoting function.