Liver X receptors participate in the fasting response by assisting CEBPB binding to enhancers and promoting the fasting transcriptional program.

Upon fasting, a group of transcription factors (TFs) activates an extensive transcriptional program in the liver to alter hepatocyte metabolism and cope with fasting. This is achieved by TF-mediated activation of enhancers, which become more accessible, leading to gene induction. Liver X receptors alpha (NR1H3) and beta (NR1H2), collectively termed here LXRs, are important TFs known to participate in transcriptional programs in the fed state, but their role in fasting is unclear. Here, we examined the effect of LXR deletion on the transcriptional and chromatin programs activated in the fasted and fed states. We profiled the liver transcriptome and genome-wide chromatin accessibility in single-knockout mice lacking either LXR isoform and in double-knockout mice lacking both isoforms. We find that double-knockout of LXRs impairs fasting-induced genes and enhancers. Analysis of genome-wide NR1H3 binding by ChIP-seq, together with chromatin accessibility profiling by ATAC-seq, shows that NR1H3 directly binds enhancers and increases their accessibility. We find that LXRs assist the binding of CCAAT/enhancer-binding protein beta (CEBPB) to enhancers during fasting. CEBPB is a key TF regulating the fasting response, and its genome-wide binding is perturbed in the absence of LXRs. Cooperation between LXRs and CEBPB promotes fasting-dependent gene induction. These findings reveal a previously unknown role for LXRs in the fasting response, whereby LXRs bind and increase enhancer accessibility, assist CEBPB binding, and promote gene induction. This study demonstrates the complex cooperation of TFs in regulating gene expression to maintain homeostasis during fasting and places LXRs as novel regulators of the fasting response.