LXRα Regulates ChREBPα Transactivity in a Target Gene-Specific Manner through an Agonist-Modulated LBD-LID Interaction

Abstract

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 the liver. More knowledge of their mechanistic interplay is needed to understand their role in pathological conditions like fatty liver disease and insulin resistance. In the current study, LXR and ChREBP co-occupancy was examined by analyzing ChIP-seq datasets from mice livers. LXR and ChREBP interaction was determined by Co-immunoprecipitation (CoIP) and their transactivity was assessed by real-time quantitative polymerase chain reaction (qPCR) of target genes and gene reporter assays. Chromatin binding capacity was determined by ChIP-qPCR assays. Our data show that LXRα and ChREBPα interact physically and show a high co-occupancy at regulatory regions in the mouse genome. LXRα co-activates ChREBPα 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 ChREBPα recruits LXRα to chromatin in trans. The two factors interact via their key activation domains; the low glucose inhibitory domain (LID) of ChREBPα and the ligand-binding domain (LBD) of LXRα. While unliganded LXRα co-activates ChREBPα, ligand-bound LXRα surprisingly represses ChREBPα activity on ChREBP-specific target genes. Mechanistically, this is due to a destabilized LXRα:ChREBPα 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 LXRα in responding to nutritional cues that was overlooked due to LXR lipogenesis-promoting function.

From Food to Genes: Transcriptional Regulation of Metabolism by Lipids and Carbohydrates

“…Additionally, PGC-1β functions as a coactivator of ChREBP, binding to the target gene promoter and physically interacting with ChREBP [ 123 ]. Interestingly, some recent evidence independently points to LXR [ 124 ] and HCF-1 [ 125 ] as noteworthy coactivators of ChREBP that have shown to enhance its transactivity not only by allosteric interaction, but also by possibly favoring its O-GlcNAcylation ( Figure 4 ). LXR which is O-GlcNAcylated in high glucose context [ 126 ] must be unliganded to induce ChREBP coactivation allowing its LBD to bind with LID of ChREBP.…”

“…LXR which is O-GlcNAcylated in high glucose context [ 126 ] must be unliganded to induce ChREBP coactivation allowing its LBD to bind with LID of ChREBP. Thus, LXR is proposed as a key lipogenesis regulator through LXR response elements when bound to oxysterols or through ChoRE otherwise [ 124 ]. For its part, HCF-1 must be O-GlcNAcylated itself as a prerequisite for ChREBP binding further establishing O-GlcNAcylation as a crucial bridge between ChREBP and at least some of the cofactors [ 125 ].…”