LXR? Regulates ChREBP? 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 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; the low glucose inhibitory domain (LID) of ChREBP? 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? in responding to nutritional cues that was overlooked due to LXR lipogenesis-promoting function.

SUBMITTER: Fan Q 

PROVIDER: S-EPMC7290792 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature