Liver X receptors connect nuclear O-GlcNAc signaling to hepatic glucose utilization and lipogenesis

Abstract

Insulin is a central regulator of glycolysis and de novo lipogenesis in the liver. However, hepatic glucose metabolism has been shown to activate the transcription of glycolytic and lipogenenic enzymes independently of insulin.  The nuclear liver X receptors LXRa and LXRb play a major role in glucose and lipid metabolism, regulating transcription of glycolytic and lipogenic enzymes in liver, which is believed to be mediated by oxysterol ligand activation and insulin signaling. The majority of hepatic glucose-responsive genes are regulated by carbohydrate response element-binding protein (ChREBP), a transcriptional regulator that requires glucose metabolism via the hexosamine biosynthetic pathway and O-GlcNAc transferase (OGT)-mediated O-GlcNAc modification for full activation. We have previously shown that also LXRs are targets for O-GlcNAc modification in response to glucose and refeeding, promoting lipogenic gene expression. We recently addressed the relative roles of insulin, glucose and LXR in regulating hepatic glycolytic and lipogenic gene expression in vivo by subjecting untreated control and streptozotocin (STZ)-treated LXRa/b^+/+ and LXRa/b^-/- mice to a fasting-refeeding regime. STZ was used to destroy pancreatic ?-cells and insulin production. We found that under hyperglycemic and hypoinsulinemic conditions, LXRs maintained their ability to upregulate the expression of glycolytic and lipogenic enzymes, including glucokinase (GK), sterol regulatory element-binding protein (SREBP-1c), ChREBPa and the newly identified shorter isoform ChREBPb. ChREBPa expression became dependent on LXR under hyperglycemic and hypoinsulinemic conditions, which was mediated, at least in part, by OGT signaling. Moreover, we found that LXR and OGT interacted and co-localized in the nucleus in Huh7 cells and that loss of LXRs profoundly reduced nuclear O-GlcNAc signaling, ChREBP O-GlcNAcylation and activity in vivo. We propose that LXR regulation of nuclear O-GlcNAc signaling and ChREBP O-GlcNAcylation is part of a mechanism linking hepatic glucose utilization with lipid synthesis.